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Supplementary Appendix This Supplementary appendix has been provided by the authors to give readers additional information about their work. Supplement to: Gopala K. Rangan, Annette T.Y. Wong, Alexandra Munt, et al. Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease. NEJM Evidence. DOI: 10.1056/EVIDoa2100021

1

Supplementary Appendix Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease

Table of Contents

Abbreviations ......................................................................................................................................... 3 Supplementary Methods ....................................................................................................................... 4

Inclusion and Exclusion Criteria1 .................................................................................................... 4 Primary Endpoint Measurement ..................................................................................................... 4 Prognostic Enrichment and Mayo Clinic Imaging Classification ................................................ 5 Study Intervention ............................................................................................................................. 6 Physiological measure of treatment adherence .............................................................................. 7 Serum copeptin .................................................................................................................................. 7 Assessment of kidney pain ................................................................................................................ 8 Determination of sample size ........................................................................................................... 8 Description of the Composite of Secondary Endpoint of Clinical Progression ........................... 9

Supplementary Results ....................................................................................................................... 11 Physiological measure of treatment adherence ............................................................................ 11 Tolvaptan use ................................................................................................................................... 12 Secondary endpoints ....................................................................................................................... 12 Adverse events by treatment group ............................................................................................... 12

Supplementary Figures ....................................................................................................................... 13 Figure S1: Lowess analysis of 24-hr urine osmolality with annual change in Log10 Ht-TKV. ...... 13

Supplementary Tables ........................................................................................................................ 14 Table S1. Demographic, clinical and laboratory characteristics of the patients at baseline ............. 14 Table S2. Mixed model with repeated measures for 24-hr urine osmolality (mOsmol/kg) from week 0 to 156 .................................................................................................................................... 16 Table S4. Proportion of patients with 24-hr-urine osmolality<300 mOsmol/kg per timepoint ....... 18 Table S5. Mixed model with repeated measures for serum copeptin from weeks 0 to 156 ............. 19 Table S6. Analysis of primary endpoint with missing data imputed using multiple imputation: Mixed model for Log10 Ht-TKV annual change per year ................................................................ 20 Table S7. Mean exposure to Tolvaptan in ad libitum and prescribed water intake groups ............. 21 Table S8. Secondary analysis of primary endpoint: Mixed model for Log10 Ht-TKV annual change per year while on treatment and before any doses of tolvaptan were taken ...................................... 22 Table S9. Sensitivity analysis of primary endpoint using as observed data: Mixed model for Log10 Ht-TKV annual change per year ....................................................................................................... 23 Table S10. Sensitivity analysis of primary endpoint using control based multiple imputation Mixed model for Log10 Ht-TKV annual change per year ........................................................................... 24 Table S11. Mixed model for eGFR annual change per year from baseline to week 156 ................. 25 Table S12. Mixed model for eGFR annual change per year from week 12 to week 156 ................ 26 Table S13. Summary of serum creatinine over time from baseline to week 160 ............................. 27 Table S14. Summary of eGFR (CKD-EPI) over time from baseline to week 160 .......................... 28 Table S15. Mixed model with repeated measures for resting mean arterial pressure (MAP) from week 0 to week 156 ........................................................................................................................... 29 Table S16. Summary of systolic blood pressure over time .............................................................. 30 Table S17. Summary of diastolic blood pressure over time ............................................................. 31 Table S18. Mixed model with repeated measures for urine albumin to creatinine ratio (mg/mmol) from week 0 to week 156 .................................................................................................................. 32 Table S19. Summary of urine albumin to creatinine ratio (mg/g) over time from baseline to week 156 ..................................................................................................................................................... 33 Table S20. Mixed model with repeated measures for kidney pain from screening to week 156 ..... 34

2

Table S21. Categorical summary of kidney pain over time ............................................................. 35 Table S22. Proportion of patients from prescribed water intake group reporting acceptability of life-long prescription ......................................................................................................................... 36 Table S23. Summary of serum sodium (mmol/L) over time ............................................................ 37 Table S24. Adverse events by organ group ...................................................................................... 38 Table S25. Adverse events1 ranked by highest number of events to lowest .................................... 39 Table S26. Adverse events by treatment group ................................................................................ 40 Table S27. Serious adverse events by treatment group .................................................................... 41

References ............................................................................................................................................ 42 Additional Acknowledgements ........................................................................................................... 43

3

Abbreviations

Abbreviation AE Adverse event AES Advanced encryption standard ADPKD Autosomal dominant polycystic kidney disease AR Autoregressive BMI Body mass index CKD Chronic kidney disease CRISP Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease d Day eGFR Estimated glomerular filtration rate Ht-TKV Height-corrected total kidney volume kg Kilograms g grams L Liter LOWESS Locally weighted scatterplot smoothing LS Least squares MedDRA Medical Dictionary for Regulatory Activities mOsmol Milliosmoles mL Milliliter mmHg Millimeter mercury MNAR Missing not a random MRI Magnetic resonance image N Number of patients Na+ Sodium SAE Serious adverse event SG Specific gravity SE Standard error TEMPO 3:4 Tolvaptan Efficacy and safety in Management of Polycystic kidney disease and its

Outcomes TRACE Time-Resolved Amplified Cryptate Emission TSI Torres Strait Islander

TKV Total kidney volume URTI Upper respiratory tract infection UTI Urinary tract infection WIMR Westmead Institute for Medical Research

4

Supplementary Methods

Inclusion and Exclusion Criteria1

Inclusion Criteria 1. Adult participants (18-67 years of age) providing informed consent 2. Adult participants with a diagnosis of ADPKD meeting the Pei-Ravine ultrasound criteria

or who were consistent with ADPKD without familial history by imaging and clinical evaluation

3. eGFR ≥ 30 mL/min/1.73 m2 within 12 weeks of randomisation

Exclusion Criteria 1. Participants present a safety risk (e.g. serum Na+ <135 mmol/L; requirement for

medications with high-risk of precipitating hyponatraemia, such as chronic use of diuretics; medical conditions that require fluid restriction, such as heart failure, chronic liver disease, nephrotic syndrome or generalized oedema; abnormalities in the voiding mechanism; pregnant or breast-feeding women)

2. Contraindication to or interference with MRI assessments (e.g. ferro-magnetic prostheses, aneurysm clips, severe claustrophobia or other contraindications)

3. Participants who are unlikely to comply with the trial’s procedures (e.g. history of non-compliance with medical therapy; history of substance abuse within the previous 2 years)

4. Participants having concomitant illnesses or treatments likely to confound endpoint assessments (poorly controlled diabetes, other known causes of CKDs, kidney cancer; single kidney; severe co-morbid illnesses)

5. Participants participating in other clinical trials to slow ADPKD or CKD 6. TKV at Baseline in the Mayo Clinic Imaging Class 1A

The Pei-Ravine unified ultrasound criteria for ADPKD is reported in reference 2 Details regarding Mayo clinic imaging class are provided in reference 3

Primary Endpoint Measurement

Kidney MRI was performed at Screening (Week -12), the 5th Study Visit (Week 78)

and the Final Study Visit (Week 156) to assess rate of change of TKV. The latter is an excellent

method to assess disease progression objectively and accurately in ADPKD and is widely

utilized in clinical trials to assess disease-specific progression. It has significant advantages

over kidney ultrasound and computerized tomography, due to precision and lack of ionizing

radiation. The MRI was performed in the Radiology Department at the Study Centre where the

participant was enrolled or an external private MRI facility. Imaging acquisition was

standardized using a set sequence protocol and method at all imaging sites. Imaging quality

was confirmed in test scans by staff at the Mayo Translational PKD. The MRI protocol was

identical to that used by the Study Centre when participating in previous ADPKD trials

5

(TEMPO 3:4 study)1 and was uniform at all sites. Participants with ferro-magnetic prostheses,

aneurysm clips, severe claustrophobia or other contraindications will be excluded from

undertaking the MRI, as outlined in the exclusion criteria.

To assess TKV, left and right kidney MRI volume will be quantified by blinded study

personnel. De-identified MR images will be encrypted and analysed by the Imaging Core of

the Mayo PKD Translational Center in Rochester, Minnesota (USA). TKV and fractional cyst

volume will be determined using manual stereology at baseline and automated segmentation

in follow-up MRI scans. De-identified images will be transferred via 256-bit AES encryption

using Dropbox file sharing system to the Mayo Clinic who undertook the image analysis of the

MRI. For determination of the height-corrected total kidney volume (Ht-TKV) 4, height was

defined as a fixed variable for the duration of the study, assuming minimal longitudinal changes

during the 3-year time-frame, 5 and it was measured using a stadiometer at the screening visit

(visit 1). Details of the statistical analysis of the primary endpoint are provided in the final

statistical analysis plan.

Prognostic Enrichment and Mayo Clinic Imaging Classification

The Mayo Clinic Imaging Classification (Subclasses 1A-1E) is an estimation of

predicted kidney growth and risk of developing end stage kidney disease according to TKV

and age.3,6 The growth rates for subclasses 1A-1E are 1.5, 3.0, 4.5 and 6.0% per

year respectively. Estimated slopes of eGFR loss by subclass (1A–1E) are −0.1, −1.2, −2.5,

−3.4 and −4.6 mL/min/1.73 m2 per year, respectively, with no significant differences between

men and women. The incidence of kidney failure at 10 years increases by subclass (1A–1E),

being 2.4, 11.0, 37.8, 47.1 and 66.9%, respectively.6 Patients with subclass 1A, who have a low

rate of kidney cyst growth (<1.5%) and 10-year risk of developing kidney failure (<5%), were

excluded during screening in order to provide prognostic enrichment of the study population.

6

Subclass Estimated annual increase in TKV 10-year risk of Kidney Failure

1A <1.5% 2.4%

1B 1.5-3% 11.0%

1C 3-4.5% 37.8%

1D 4.5-6% 47.1%

1E >6% 66.9%

Study Intervention

Participants allocated to the prescribed water intake group had a detailed consultation with the

Study Dietitian that included the following:

• Calculation of the Water Prescription:7 Individuals were advised to drink a prescribed

volume of water per day based on the free water clearance formula, to reduce the urine

osmolality ≤270 mOsmol/kg (or to maintain euhydration). The fluid prescription (in mls) was

as follows: Recommended Water Intake = [Total solutes (mOsmol)/270] mL] , where total solutes

(=urine osmolality x urine volume in mLs) was the mean derived from two 24-hr urine measurements,

collected following the Screening Visit. The volume advised for the patient to drink per day was rounded

to the nearest decilitre.

• Diet counselling: A high dietary solute load (due to high salt and protein intakes) requires

a greater fluid intake to maintain dilute urine. Therefore, patients were educated about the

importance of dietary solute intake in determining obligatory urine volume (i.e. the minimal

amount of urine required to excrete the daily solute load). 8 The Study Dietitian undertook

a detailed diet history initially, and a 24-hour recall at subsequent visits to provide

individually tailored dietary advice to enable subjects to achieve and maintain a moderate

protein intake (0.75-1.0 g/kg/d) and limit sodium intake to 80-100 mmol/d.

• Review of lifestyle and environmental factors: The participant’s lifestyle, personal

preferences and occupation was considered when providing individualized techniques for

promoting adherence to fluid intake. Participants were provided with 3x1L re-usable water

1L filtered drink bottles (Bobble, Chicago, IL, USA) as an optional tool to help keep track

7

of their fluid intake and will be encouraged to drink evenly throughout the day and replenish

with each episode of nocturia.

• Self-monitoring of water intake and treatment efficacy: Individualized aids to assist

participants with self-monitoring were developed. These included a paper-based diary or

web-based/smartphone compatible tool to self-monitor fluid intake, provided drink bottles,

and urine dipsticks to record urine specific gravity (SG). Patients were educated on how to

read their urine SG and were asked to test this, ideally, during the late-afternoon (4-8 pm)

at least once daily in the first 2 weeks of the study, at least twice weekly for the first 6

months and then monthly for the duration of the study. If patients were non-compliant to

their prescribed water intake and/or urine osmolality is > 270mOsmol/kg, study dietitians

requested urine SG results more frequently (i.e. returning to weekly) as a method of

monitoring and motivation in agreeance with the participant. A urine SG value of ≤1.010

indicated a spot urine osmolality of ≤280 mOsmol/kg, and the fluid intake in the past few

hours has been adequate. Furthermore, patients were briefed on receiving and responding

to SMS text messages or telephone calls (or emails if they do not own a mobile phone)

requesting the results of a late-afternoon urine SG.

Physiological measure of treatment adherence

A physiological measure of treatment adherence during the study period was defined

as changes in markers of systemic arginine vasopressin activity (24-hour urine osmolality and

volume and serum copeptin) from baseline together with the number and percentage of patients

with 24-hour urine osmolality <300 mOsmol/kg at each and >50% of timepoints (between

weeks 12-156, that is during the treatment period).

Serum copeptin

Blood samples collected at all study visits were centrifuged and the serum was stored -

800C at the Westmead Institute for Medical Research (WIMR). For inter-state samples, serum

8

samples were shipped in bulk to WIMR on dry ice and stored until further analysis. All serum

samples from all timepoints were thawed once and measured in bulk using a commercial Time-

Resolved Amplified Cryptate Emission (TRACE) assay (BRAHMS Thermofisher

KRYPTOR Copeptin; B.R.A.H.MS. GmbH, Henningsdorf, Germany) at the Department of

Chemical Pathology, Royal Prince Alfred Hospital (Sydney, Australia). The limit of detection

of the assay was 0.69pmol/L, and the limit of quantitation was 1.23pmol/L (CV of 20%). The

inter-assay precision at copeptin levels of 5.36pmol/L and 104.23pmol/L are 5.04% and 4.49%

respectively. The reference interval in the healthy adult population was 1.1-16.3pmol/L.9

Assessment of kidney pain

A simple clinical tool for the assessment of kidney pain was developed by Dr. Jared

Grantham for this study based, in part, on the pain scale used in the TEMPO 3:4 clinical trial.

1 The Grantham PKD Pain Scale was used at all study visits including the Screening Visit, and

kidney pain was assessed according to the following: 0 = no pain; 1 = noticeable but not

distracting pain; 2 = pain requiring over the counter analgesics; 3 = pain requiring a doctor’s

visit; 4 = pain requiring narcotics; 5 = pain requiring hospital admission.

Determination of sample size

In the longitudinal data from the CRISP-II cohort, the average rate of increase in Ht-TKV

was 5.5+3.8% per year (mean ± standard deviation, n=201; 8-yr follow-up).4 Preclinical and clinical

studies indicate that inhibition of AVP-mediated cyst growth, either by pharmacological inhibition

or adequate hydration, both have similar treatment efficacy of ~50% on kidney volume.1,10,11 In this

trial, we nominated a more modest (but still clinically significant) treatment effect of 35%. Using

these assumptions, a total sample size of 150 had 87% power to detect a difference in Ht-TKV of

9

1.9% per year using a two-sided test and a 0.05 level of significance. Considering the possibility

of 15% dropouts, the aim was to include 180 participants (n=90 per arm).

Exploratory analysis

To assess treatment effectiveness, the association between 24-hour urine osmolality and

the primary outcome (Ht-TKV annual change) was determined at week 156. For the graph, Ht-

TKV annual change was calculated as: Ht-TKV Annual Change = [(Ht-TKV 3 year value - Ht-

TKV screening value)/(Date Year 3 – Screening Date )]*365.25. This was assessed graphically

by a scatterplot with a superimposed locally weighted scatterplot smoothing (LOWESS)

regression. Smoothers are lines plotted onto a scatterplot to show the general trend of the

relationship between the variables. If the smoothed line is roughly linear then the association

between each of the 24-hour urine and the Ht-TKV annual change will be assessed with simple

linear regression.

Description of the Composite of Secondary Endpoint of Clinical Progression

The details and method of analysis of the composite secondary endpoint are described in detail

in the final study protocol and statistical analysis plan. Briefly, the five components of the

composite secondary endpoint of time to investigator-assessed clinical progress were defined

as listed below and were based on the TEMPO 3:4 study protocol1 and consisted of the

following events:

(i) worsening kidney function from baseline, defined as a ≥25% reduction in eGFR

from baseline;

(ii) worsening kidney function from week 12, defined as a ≥25% reduction in eGFR

from week 12; the latter was chosen to consider any acute effects of prescribed

water intake on eGFR

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(iii) worsening hypertension, defined as changes in blood pressure category (as shown

below) or worsening hypertension requiring an increase in anti-hypertensive

medication treatment. The higher of the systolic or diastolic blood pressure was

used to determine the category.

Blood Pressure Category Systolic (mmHg) Diastolic (mmHg) Non-hypertensive <120 <80

Low pre-hypertensive 120-129 80-84 High-pre-hypertensive 130-139 85-89

Hypertensive >139 >89

(iv) Worsening albuminuria as defined by the categories of albuminuria (see below)

Albuminuria Stages Normal Microalbuminuria Macroalbuminuria

<26.55 mg/g 26.55-265.49 mg/g >265.49 mg/g

(v) Clinically significant kidney pain necessitating medical leave, pharmacologic

treatment (narcotic or last-resort analgesic agents), or invasive intervention will be

defined as having a Kidney Pain Assessment of: ‘Pain requiring over the counter

analgesics’, ‘Pain requiring a doctor’s visit’, ‘Pain requiring narcotics’, or ‘Pain

requiring hospital admission.’

These five types of events were pooled together as events of investigator-assessed clinical

progression. If a patient had more than one event occurring at the same visit (for example, an

event of worsening kidney function from baseline and an event of worsening hypertension),

only one of the events was retained in the analysis. The visit date of the event was used to

calculate the time to event. For example, the time to event in days = (date of the visit where

event occurred – date of randomisation visit + 1).

11

Supplementary Results

Physiological measure of treatment adherence

At baseline, 24-hour urine volume and osmolality, and the percentage of patients with 24-hour

urine osmolality <300mOsmol/kg (20.9 and 29.4%) was similar in the two groups (Table S4). During

the treatment period (weeks 12 to 156), 24-hour urine osmolality consistently decreased (and 24-hour

urine increased) in the prescribed water intake group compared to the ad libitum intake groups (Tables

S2 and S3). The percentage of patients with 24-hour urine osmolality <300mOsmol/kg increased in the

prescribed water intake group to 51.4% while remaining low at 13.7% in the ad libitum water intake

group at week 12 (Table S4). The proportion of patients with 24-hour urine osmolality <300mOsmol/kg

remained consistently higher in the prescribed water intake group compared to ad libitum intake

throughout the treatment period (Week 12 to Week 156) (Table S4). The percentage of patients with a

24-hour urine osmolality <300mOsmol/kg for >50% of the time points was 52.3% in the prescribed

water intake group and 17.4% in the ad libitum water intake group (Table S4).

Serum copeptin, a surrogate marker of AVP was not different between the study groups at

baseline with values of 13.0pmol/L and 11.0pmol/L in the ad libitum and prescribed water intake groups

respectively (difference of -2.0pmol/L; 95% CI, -4.6 to 0.6pmol/L).

Relationship between annual change in Ht-TKV and 24-hour urine osmolality

As a pre-specified exploratory analysis and to further evaluate the primary hypothesis, we

performed Locally Weighted Scatterplot Smoothing (Lowess) analysis of 24-hour urine osmolality by

change in Ht-TKV. As shown in Figure S1, there appeared to be no relationship between log10 Ht-TKV

annual change and mean urine osmolality as the Lowess lines are flat relative to the variability of the

scatter-points in the graph.

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Tolvaptan use

Eight patients started tolvaptan during the study period including five in the prescribed water

intake group and three in the ad libitum water intake groups. One patient in the prescribed water intake

group started tolvaptan after the treatment period (that is after, week 156). Three out of the five patients

in the prescribed water intake group and two out of three in the ad libitum water intake group completed

MRI before starting tolvaptan. Two patients, one from each study group ceased tolvaptan, due to

intolerable aquaretic symptoms and abnormal liver function tests.

Secondary endpoints

Of the additional pre-specified secondary endpoints, mean arterial pressure and urinary albumin

to creatinine ratio did not change in between the prescribed and ad libitum water intake groups at any

of the timepoints from screening to Week 156 (Tables S15-S21). Kidney pain was transiently lower in

the prescribed water intake group at Week 78 and Week 156 with a difference between the prescribed

and ad libitum water intake groups of -0.2 (95% CI, -0.5 to -0.0) and -0.3 (95% CI, -0.5 to -0.1)

respectively (Table S20).

Adverse events by treatment group

Of the adverse events experienced by ≥5% of the study population, ≥10 patients in the

prescribed water intake group experienced hypertension, flank pain, fatigue, hematuria, gastroenteritis,

urinary tract infection (UTI), nausea and abdominal pain; whereas ≥10 patients in the ad libitum water

intake group experienced hypertension, gastroenteritis, abdominal pain, flank pain, arthralgia,

headache, hypercholesterolemia, iron deficiency and UTI (Table S26).

13

Supplementary Figures

Figure S1: Lowess analysis of 24-hr urine osmolality with annual change in Log10 Ht-TKV. Mean osmolality is the mean twenty-four hour urine osmolality for each patient from Week 0 to Week 156. Log10 Ht-TKV annual change= [(Log10 Ht-TKV 3 year value – Log10 Ht-TKV screening value)/(Date Year 3 – Screening Date)]*365.25. Results are based on as observed data with no imputation of missing values.

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Supplementary Tables

Table S1. Demographic, clinical and laboratory characteristics of the patients at baseline

Characteristic ad libitum water intake

(N=92)

Prescribed water intake

(N=92) Age - years 42.8±11.2 43.4±10.9 Female sex -no. (%) 44 (47.8) 50 (54.3) Race or ethnic group a -no. (%) Caucasian Asian Australian Aborigine/TSI Pacific Islander Other

69 (75.0) 12 (13.0) 1 (1.1) 0 (0.0)

10 (10.9)

65 (70.7) 14 (15.2) 1 (1.1) 1 (1.1)

11 (12.0) Medical history related to PKD – no. (%) Total with any PKD medical history b Hypertension Hematuria Flank pain Kidney pain Urinary tract infection Nephrolithiasis Kidney cyst rupture Proteinuria Cardiac/Vascular disease Medical History not related to PKD – no. (%) Total with any non-PKD medical history c

90 (97.8) 72 (78.3) 37 (40.2) 50 (54.3) 49 (53.3) 34 (37.0) 20 (21.7) 27 (29.3) 32 (34.8) 7 (7.6)

84 (91.3)

91 (98.9) 67 (72.8) 36 (39.1) 37 (40.2) 35 (38.0) 39 (42.4) 13 (14.1) 31 (33.7) 20 (21.7) 14 (15.2)

87 (94.6)

Mean height - cm 171.4±11.9 169.6±9.2 Mean weight – kg 81.5±20.4 76.9±16.7 Mean BMI - kg/m2 27.5±5.1 26.6±4.6 Mean blood pressure - mm Hg Systolic Diastolic

131±13 83±11

130±12 80±10

Current anti-hypertensives– no (%) d Any anti-hypertensive drug treatment Angiotensin converting enzyme inhibitor Angiotensin receptor blocker Beta-blocker Calcium-channel blocker Other

68 (73.9) 35 (38.0) 30 (32.6) 4 (4.3)

28 (30.4) 5 (5.4)

64 (69.5) 30 (32.6) 33 (35.9) 8 (8.7)

22 (23.9) 2 (2.2)

Median Ht-TKV volume - mL/m (IQR) 700.5 (485.0-1090.0) 629.0 (436.5-1124.0) Mayo imaging subclass – no. (%) 1B 1C 1D 1E

26 (28.3) 38 (41.3) 18 (19.6) 10 (10.9)

31 (33.7) 36 (39.1) 17 (18.5) 8 (8.7)

Mean serum creatinine (Cr) - mg/dL 1.12±0.37 1.10±0.38 Mean estimated GFR e - mL/min/1.73m2 77.8±25.3 77.7±24.8 Mean urinary albumin-to-Cr ratio - mg/g 45.0±58.3 51.0±116.7 Median 24-hour urine volume - mL (IQR) 2280 (1924-2998) 2228 (1548-3100) Mean 24-hour urine osmolality - mOsmol/kg 416±147 429±181 Mean serum sodium - mmol/L 140±2 140±2 Mean serum osmolality - mOsmol/kg 294±7 294±7 Median serum copeptin - pmol/L 6.5 (3.8-12.4) 5.9 (3.1-13.0)

15

Plus-minus values are means±SD a Race was self-reported b Denotes total number of patients with a history of medical events reasonably attributable to PKD c Denotes total number of patients with a history of medical history not direct attributable to PKD (the top 10 conditions were asthma, hypercholesterolemia, tonsillitis, upper respiratory tract infection, back pain, gastroesophageal reflux, gout, joint injury, depression and seasonal allergy) d Diuretics - one patient in the ad libitum water intake group and 6 patients in the prescribed water intake group were treated with diuretics at the Screening Visit. In consultation with the patients treating nephrologist and in accordance with the study protocol, , the diuretics were withdrawn to reduce the risk of hyponatremia occurring the treatment period. e The estimated GFR was calculated using the Chronic Kidney Disease Epidemiology equation BMI – Body Mass Index Ht-TKV, height-adjusted total kidney volume TSI – Torres Strait Islander

16

Table S2. Mixed model with repeated measures for 24-hr urine osmolality (mOsmol/kg) from week 0 to 156

Visit 24-hour urine osmolality

ad libitum water intake

(N=92)


(N=92) Overall*

LS Mean (SE) 418.6 (15.9) 328.0 (16.0) LS Mean Difference (SE) -90.6 (18.6) 95% Confidence Interval for Treatment Difference (-127.3,-54.0) P-value for Treatment Difference <.001 P-value for Visit <.001 P-value for Treatment by Visit Interaction <.001

Week 0

LS Mean (SE) 422.5 (19.9) 420.7 (20.0) LS Mean Difference (SE) -1.8 (25.2) 95% Confidence Interval for Treatment Difference (-51.6,48.0) P-value for Treatment Difference 0.944

Week 12

LS Mean (SE) 435.6 (18.4) 319.4 (18.4) LS Mean Difference (SE) -116.2 (22.7) 95% Confidence Interval for Treatment Difference (-161.1,-71.3) P-value for Treatment Difference <.001

Week 26


Week 36


Week 52


Week 78


Week 104

LS Mean (SE) 385.2 (17.9) 315.3 (18.1) LS Mean Difference (SE) -69.9 (21.9) 95% Confidence Interval for Treatment Difference (-113.2,-26.6) P-value for Treatment Difference 0.002

Week 130


Week 156


*Weeks 0, 12, 26, 36, 52, 78, 104, 130, and 156 combined. No imputation of missing data was performed. Results are from a mixed model with repeated measures, with 24-hour urine osmolality over time (Weeks 0, 12, 26, 36, 52, 78, 104, 130, and 156) as the dependent variable; and the independent variables: baseline Mayo Clinic Imaging Subclass 1B-1E, baseline eGFR stratification category (<60 or ≥60 mL/min/1.73m2), baseline log 10 Ht-TKV, treatment group, visit, and treatment*visit interaction. An unstructured variance-covariance matrix was used. LS Mean Difference = LS mean of prescribed water intake – LS mean of ad libitum water intake. LS, least squares; SE, standard error.

17

Table S3. Mixed model with repeated measures for 24-hr urine volume (mLs) from week 0 to 156

Visit 24-hour urine volume


(N=92)


(N=92) Overall*

LS Mean (SE) 2364.0 (111.0) 2996.6 (111.7) LS Mean Difference (SE) 632.6 (133.4) 95% Confidence Interval for Treatment Difference (368.8,896.4) P-value for Treatment Difference <.001 P-value for Visit <.001 P-value for Treatment by Visit Interaction <.001

Week 0


Week 12

LS Mean (SE) 2295.5 (128.3) 2971.8 (128.7) LS Mean Difference (SE) 676.3 (161.4) 95% Confidence Interval for Treatment Difference (357.3,995.4) P-value for Treatment Difference <.001

Week 26


Week 36


Week 52


Week 78


Week 104

LS Mean (SE) 2577.5 (142.8) 3066.0 (143.8) LS Mean Difference (SE) 488.5 (184.5) 95% Confidence Interval for Treatment Difference (123.7,853.3) P-value for Treatment Difference 0.009

Week 130


Week 156


*Weeks 0, 12, 26, 36, 52, 78, 104, 130, and 156 combined. No imputation of missing data was performed. Results are from a mixed model with repeated measures, with 24-hour urine volume over time (Weeks 0, 12, 26, 36, 52, 78, 104, 130, and 156) as the dependent variable; and the independent variables: baseline Mayo Clinic Imaging Subclass 1B-1E, baseline eGFR stratification category (<60 or ≥60 mL/min/1.73m2), baseline log 10 Ht-TKV, baseline 24-hour urine osmolality, treatment group, visit, and treatment*visit interaction. An unstructured variance-covariance matrix was used. LS Mean Difference = LS mean of prescribed water intake – LS mean of ad libitum water intake. LS, least squares; SE, standard error.

18

Table S4. Proportion of patients with 24-hr-urine osmolality<300 mOsmol/kg per timepoint

n, number of patients with <300 mOsmol/kg (mmol/kg) at each time point

Visit ad libitum water intake Prescribed water intake n/Total number (%) n/Total number (%)

Baseline/Screening 1 23/91 25.27 26/92 28.26 Baseline/Screening 2 18/86 20.93 25/85 29.41

Week 12 10/73 13.70 38/74 51.35 Week 26 14/78 17.95 35/70 50.00 Week 36 15/66 22.73 31/65 47.69 Week 52 13/70 18.57 35/65 53.85 Week 78 20/74 27.03 36/70 51.43 Week 104 18/66 27.27 39/65 60.00 Week 130 18/68 26.47 39/65 60.00 Week 156 19/67 28.36 37/70 52.86

Physiological Measure of Treatment Adherence: Proportion of patients <300 mOsmol/kg for

>50% time points (Weeks 12 to 156)

15/86

17.44

45/86

52.33

19

Table S5. Mixed model with repeated measures for serum copeptin from weeks 0 to 156

Visit Serum copeptin (pmol/L)


(N=92)


(N=92) Overall*

LS Mean (SE) 13.0 (1.1) 11.0 (1.1) 95% Confidence Interval for LS Mean (10.7, 15.2) (8.7, 13.2) LS Mean Difference (SE): Prescribed minus ad libitum

-2.0 (1.3)

95% Confidence Interval for Treatment Difference (-4.6,0.6) P-value for Treatment Difference 0.137 P-value for Visit 0.027 P-value for Treatment by Visit Interaction 0.750

Week 0

LS Mean (SE) 12.8 (1.2) 12.3 (1.3) LS Mean Difference (SE): Prescribed minus ad libitum

-0.5 (1.5)

95% Confidence Interval for Treatment Difference (-3.5,2.5) P-value for Treatment Difference 0.731

Week 26


-1.9 (1.5)


Week 52


-1.6 (1.3)


Week 78


-3.2 (2.3)


Week 104


-1.9 (1.6)


Week 130


-2.1 (1.6)


Week 156


-2.7 (1.6)


* Months 0, 6, 12, 18, 24, 30, and 36 combined. No imputation of missing data was performed. Results are from a mixed model with repeated measures, with 24-hour urine volume over time (Months 0, 6, 12, 18, 24, 30, and 36) as the dependent variable; and the independent variables: baseline Mayo Clinic Imaging Subclass 1B-1E, baseline eGFR stratification category (<60 or ≥60 mL/min/1.73m2), baseline log 10 Ht-TKV, baseline 24-hour urine osmolality, treatment group, visit, and treatment*visit interaction. A Compound-Symmetry variance-covariance matrix was used. LS Mean Difference = LS mean of prescribed water intake – LS mean of ad libitum water intake. LS, least squares; SE, standard error.

20

Table S6. Analysis of primary endpoint with missing data imputed using multiple imputation:

Mixed model for Log10 Ht-TKV annual change per year

Results are from a linear mixed effect model with log10 Ht-TKV over time as the dependent variable; the fixed effects: Mayo Clinic Imaging Subclasses 1B-1E, baseline eGFR category (<60 or ≥ 60 mL/min/1.73m2), mean baseline 24-hour urine osmolality, treatment group, and treatment*time interaction; and random intercept and slope. Geometric mean, geometric mean ratio, and 95% confidence interval for Ht-TKV annualized change per year were calculated by raising 10 to the power of the means, mean treatment difference, and 95% confidence interval for log10 Ht-TKV annualized change. Missing data were imputed using multiple imputations with 100 samples redrawn. Ht-TKV, height-adjusted total kidney volume; log10 Ht-TKV, logarithm to the base 10 of height-adjusted total kidney volume; SE, standard error.


(N=92)


(N=92) Log10 Ht-TKV annualized change per year Mean (SE) 0.033 (0.002) 0.028 (0.002) 95% Confidence Interval for Mean (0.028, 0.037) (0.025, 0.032) Mean Difference (SE) -0.004 (0.003) 95% Confidence Interval for Difference (-0.010, 0.002) P-value for Treatment Difference 0.177 Ht-TKV annualized change per year Geometric Mean 1.078 1.068 95% Confidence Interval for Geometric Mean (1.067, 1.090) (1.058, 1.077) Geometric Mean Ratio 0.990 95% Confidence Interval for Geometric Mean Ratio (0.976, 1.004) Ht-TKV annualized change (% per year) Estimated annualized % change (EA%C) 7.825 6.775 95% Confidence Interval for EA%C (6.660, 8.993) (5.828, 7.721) %Change in rate of growth (Prescribed vs. ad libitum) -0.973 95% Confidence Interval %change in rate of growth (-2.370, 0.443)

21

Table S7. Mean exposure to Tolvaptan in ad libitum and prescribed water intake groups

Group A, ad libitum water intake; Group B, prescribed water intake; MRI, magnetic resonance imaging a This patient started Tolvaptan after the treatment period at the week 156 study visit, but before follow-up visit at Week 160

Participant ID

Group Start Date of study

intervention (Visit 2)

Tolvaptan Start Date

Date of MRI (Scheduled vs. unscheduled)

Was MRI completed before or

after starting

tolvaptan?

Continuing at end of study?

Cease date

Cease reason

Months of Exposure (time to Week 156)

Highest Dose

Attained (mg/mg)

038 B 11-Nov-2016

19-Dec-2019

Month 36 MRI completed

19-Nov-2019

30 days before

Y N/A N/A 0a 45/15

105 B 24-Oct- 2017

01-May-2020

Unscheduled MRI completed

03-Jun-2020

33 days after Y N/A N/A 7 30/15

115 A 01-Dec-2017

01-Sep-2019


27-May-2019

97 days before

N 02-Sep-2019

(proxy)

Aquaretic symptoms

1 Unknown

117 B 12-Dec-2017

24-Jun-2019


17-May-2019

38 days before

N 19-May-2020

Elevated liver

enzymes

12 30/15

138 B 10-Jan- 2018

21-Dec-2018


30-Nov-2018

21 days before

Y N/A N/A 25 45/15

149 A 06-Feb- 2018

23-May-2019


08-Aug-2019


157 B 08-Mar-2018

24-Dec-2018


14-Jan-2019


179 A 16-04- 2018

21-Jun-2019


13-Mar-2019

100 days before

Y N/A N/A 20 60/30

22

Table S8. Secondary analysis of primary endpoint: Mixed model for Log10 Ht-TKV annual change per year while on treatment and before any doses of tolvaptan were taken

Results are from a linear mixed effect model with log10 Ht-TKV over time as the dependent variable; the fixed

effects: Mayo Clinic Imaging Subclasses 1B-1E, baseline eGFR category (<60 or ≥ 60 mL/min/1.73m2), baseline

24-hour urine osmolality, treatment group, and treatment*time interaction; and random intercept and slope.

Geometric mean, geometric mean ratio, and 95% confidence interval for Ht-TKV annualized change per year

were calculated by raising 10 to the power of the means, mean treatment difference, and 95% confidence interval

for log10 Ht-TKV annualized change. Ht-TKV, height-adjusted total kidney volume; log10 Ht-TKV, logarithm

to the base 10 of height-adjusted total kidney volume; SE, standard error.


(N=92)


(N=92) Log10 Ht-TKV annualized change per year Mean (SE) 0.033 (0.002) 0.028 (0.002) 95% Confidence Interval for Mean (0.028, 0.037) (0.024, 0.032) Mean Difference (SE) -0.005 (0.003) 95% Confidence Interval for Difference (-0.011, 0.001) P-value for Treatment Difference 0.131 Ht-TKV annualized change per year Geometric Mean 1.078 1.066 95% Confidence Interval for Geometric Mean (1.067, 1.090) (1.056, 1.077) Geometric Mean Ratio 0.989 95% Confidence Interval for Geometric Mean Ratio (0.975, 1.003) Ht-TKV annualized change (% per year) Estimated annualized % change (EA%C) 7.829 6.631 95% Confidence Interval for EA%C (6.684, 8.993) (5.584, 7.671) %Change in rate of growth

(Prescribed vs. ad libitum) -1.111

95% Confidence Interval %change in rate of growth (-2.538, 0.337)

23

Table S9. Sensitivity analysis of primary endpoint using as observed data: Mixed model for Log10 Ht-TKV annual change per year

Results are from a linear mixed effect model with log10 Ht-TKV over time as the dependent variable; the fixed

effects: Mayo Clinic Imaging Subclasses 1B-1E, baseline eGFR category (<60 or ≥ 60 mL/min/1.73m2), baseline

24-hour urine osmolality, treatment group, and treatment*time interaction; and random intercept and slope.

Geometric mean, geometric mean ratio, and 95% confidence interval for Ht-TKV annualized change per year

were calculated by raising 10 to the power of the means, mean treatment difference, and 95% confidence interval

for log10 Ht-TKV annualized change. Ht-TKV, height-adjusted total kidney volume; log10 Ht-TKV, logarithm

to the base 10 of height-adjusted total kidney volume; SE, standard error.


(N=92)


(N=92) Log10 Ht-TKV annualized change per year Mean (SE) 0.032 (0.002) 0.028 (0.002) 95% Confidence Interval for Mean (0.028, 0.037) (0.024, 0.032) Mean Difference (SE) -0.004 (0.003) 95% Confidence Interval for Difference (-0.010, 0.002) P-value for Treatment Difference 0.169 Ht-TKV annualized change per year Geometric Mean 1.077 1.067 95% Confidence Interval for Geometric Mean (1.066, 1.089) (1.058, 1.076) Geometric Mean Ratio 0.990 95% Confidence Interval for Geometric Mean Ratio (0.977, 1.004) Ht-TKV annualized change (% per year) Estimated annualized % change (EA%C) 7.721 6.688 95% Confidence Interval for EA%C (6.586, 8.868) (5.755, 7.622) %Change in rate of growth (Prescribed vs. ad libitum)

-0.959


24

Table S10. Sensitivity analysis of primary endpoint using control based multiple imputation Mixed model for Log10 Ht-TKV annual change per year

Missing data was imputed under the Missing Not at Random (MNAR) assumption using control based multiple

imputation with 100 samples redrawn. Missing data for both treatment groups was imputed based on the

imputation model derived from the ad libitum fluid intake group only. Results are from a linear mixed effect

model with log10 Ht-TKV over time as the dependent variable; the fixed effects: Mayo Clinic Imaging Subclasses

1B-1E, baseline eGFR category (<60 or ≥ 60 mL/min/1.73m2), mean baseline 24-hour urine osmolality, treatment

group, and treatment*time interaction; and random intercept and slope. Geometric mean, geometric mean ratio,

and 95% confidence interval for Ht-TKV annualized change per year were calculated by raising 10 to the power

of the means, mean treatment difference, and 95% confidence interval for log10 Ht-TKV annualized change. Ht-

TKV, height-adjusted total kidney volume; log10 Ht-TKV, logarithm to the base 10 of height-adjusted total

kidney volume; SE, standard error.


(N=92)


(N=92) Log10 Ht-TKV annualized change per year Mean (SE) 0.033 (0.002) 0.029 (0.002) 95% Confidence Interval for Mean (0.028, 0.038) (0.024, 0.033) Mean Difference (SE) -0.004 (0.003) 95% Confidence Interval for Difference (-0.010, 0.002) P-value for Treatment Difference 0.189 Ht-TKV annualized change per year Geometric Mean 1.078 1.068 95% Confidence Interval for Geometric Mean (1.067, 1.090) (1.058, 1.078) Geometric Mean Ratio 0.990 95% Confidence Interval for Geometric Mean Ratio (0.976, 1.005) Ht-TKV annualized change (% per year) Estimated annualized % change (EA%C) 7.850 6.809 95% Confidence Interval for EA%C (6.660, 9.044) (5.779, 7.845) %Change in rate of growth (Prescribed vs. ad libitum)

-0.965


25

Table S11. Mixed model for eGFR annual change per year from baseline to week 156

No imputation of missing data was performed.

Results are from a linear mixed effect model with eGFR change over time (Screening, Weeks 12, 26, 36, 52, 78,

104, 130 and 156) as the dependent variable; the fixed effects: Mayo Clinic Imaging Subclasses IB-IE category

(<60 or >=60 ml/min/1.73m2), baseline 24-hour urine osmolality, baseline log10 Ht-TKV, treatment group, and

treatment*time interaction; and random intercept and slope.

eGFR was determined by the chronic kidney disease epidemiology collaboration (CKD EPI) formula


(N=92)


(N=92) eGFR annualized change per year from baseline to week 156 (mL/min/1.73m2/year) Mean (SE) -2.380 (0.381) -2.309 (0.386) 95% Confidence Interval for Mean (-3.128, -1.632) (-3.066, -1.552) Mean Difference (SE) 0.070 (0.543) 95% Confidence Interval for Difference (-0.996, 1.136) P-value for Treatment Difference 0.897

26

Table S12. Mixed model for eGFR annual change per year from week 12 to week 156

No imputation of missing data was performed.

Results are from a linear mixed effect model with eGFR change over time (Weeks 12, 26, 36, 52, 78, 104, 130

and 156) as the dependent variable; the fixed effects: Mayo Clinic Imaging Subclasses IB-IE category (<60 or

>=60 ml/min/1.73m2), baseline 24-hour urine osmolality, baseline log10 Ht-TKV, treatment group, and

treatment*time interaction; and random intercept and slope.

eGFR was determined by the chronic kidney disease epidemiology collaboration (CKD EPI) formula


(N=92)


(N=92) eGFR annualized change per year from week 12 to week 156 (mL/min/1.73m2/year) Mean (SE) -2.525 (0.440) -2.237 (0.419) 95% Confidence Interval for Mean (-3.390, -1.661) (-3.059, -1.414) Mean Difference (SE) 0.289 (0.609) 95% Confidence Interval for Difference (-0.906, 1.484) P-value for Treatment Difference 0.636

27

Table S13. Summary of serum creatinine over time from baseline to week 160

Creatinine (mg/dL)

Actual Values Change from Screening

Group Scheduled Visit n Mean SD

Media

n Min Max IQR n Mean SD

Media

n Min Max

ad libitum water intake Baseline 92 1.12 0.37 1.06 0.59 2.21 (0.87; 1.30) Week 12 76 1.15 0.42 1.07 0.62 2.66 (0.80; 1.45) 76 0.01 0.12 0.02 -0.37 0.45 Week 26 78 1.16 0.44 1.07 0.51 2.49 (0.84; 1.36) 78 0.02 0.11 0.01 -0.23 0.43 Week 36 70 1.14 0.42 1.07 0.51 2.49 (0.79; 1.36) 70 0.02 0.13 0.01 -0.37 0.51 Week 52 72 1.22 0.51 1.07 0.51 2.88 (0.85; 1.45) 72 0.07 0.18 0.03 -0.23 0.68 Week 78 78 1.23 0.53 1.13 0.54 3.08 (0.79; 1.54) 78 0.10 0.19 0.06 -0.17 0.87 Week 104 68 1.26 0.65 1.13 0.41 4.07 (0.79; 1.58) 68 0.13 0.34 0.06 -0.23 1.87 Week 130 70 1.33 0.72 1.13 0.52 4.52 (0.85; 1.53) 70 0.21 0.41 0.08 -0.20 2.32 Week 156 69 1.39 0.84 1.17 0.57 5.32 (0.85; 1.58) 69 0.26 0.51 0.06 -0.11 3.11 Week 160 60 1.47 0.91 1.17 0.57 4.92 (0.88; 1.70) 60 0.31 0.60 0.11 -0.10 2.71

Prescribed water intake Baseline 91 1.10 0.39 0.99 0.57 2.38 (0.84; 1.33) Week 3 74 1.13 0.43 1.02 0.54 2.43 (0.85; 1.30) 74 0.01 0.11 0.00 -0.32 0.34 Week 6 78 1.13 0.42 1.02 0.57 2.60 (0.83; 1.36) 77 0.01 0.11 0.00 -0.28 0.37 Week 12 70 1.19 0.47 1.05 0.62 2.60 (0.85; 1.36) 70 0.03 0.12 0.01 -0.14 0.34 Week 26 74 1.14 0.45 1.02 0.51 2.43 (0.85; 1.30) 74 0.03 0.11 0.03 -0.37 0.45 Week 36 64 1.20 0.48 1.02 0.62 2.71 (0.87; 1.41) 64 0.05 0.13 0.05 -0.35 0.51 Week 52 64 1.19 0.49 1.06 0.57 3.17 (0.85; 1.41) 63 0.07 0.17 0.06 -0.45 0.79 Week 78 68 1.19 0.57 1.04 0.60 3.51 (0.85; 1.39) 68 0.08 0.23 0.03 -0.42 1.16 Week 104 65 1.31 0.71 1.07 0.57 4.24 (0.85; 1.53) 65 0.17 0.37 0.08 -0.46 1.87 Week 130 64 1.38 0.80 1.09 0.57 5.49 (0.90; 1.61) 64 0.21 0.49 0.08 -0.49 3.11 Week 156 70 1.36 0.95 1.04 0.62 6.52 (0.85; 1.58) 69 0.25 0.64 0.08 -0.44 4.14 Week 160 55 1.52 1.16 1.18 0.54 7.52 (0.90; 1.67) 55 0.35 0.84 0.11 -0.32 5.15

28

Table S14. Summary of eGFR (CKD-EPI) over time from baseline to week 160

eGFR (mL/min/1.73m2)

Actual Values Change from Screening

Group Scheduled Visit n Mean SD

Media

n Min Max IQR n Mean SD

Media

n Min Max

ad libitum water intake Baseline 92 77.80 25.341 76.3 30.5 130.1 (56.8; 96.7) Week 12 76 75.99 26.344 73.2 30.0 125.6 (54.3; 99.4) 76 -0.43 7.219 -0.4 -16.1 20.4 Week 26 78 76.77 27.015 77.2 27.7 130.1 (54.8; 94.1) 78 -0.38 6.378 -0.9 -15.1 20.2 Week 36 70 75.24 26.820 70.4 26.7 128.7 (54.3; 98.3) 70 -1.02 6.636 -0.2 -15.7 20.2 Week 52 72 72.79 28.212 70.7 24.5 128.7 (49.4; 93.7) 72 -1.90 8.087 -2.1 -18.2 20.2 Week 78 78 73.45 29.866 71.7 22.6 133.8 (47.8; 98.3) 78 -3.63 7.987 -3.9 -22.8 15.1 Week 104 67 71.88 30.202 70.8 16.5 133.8 (46.5; 90.6) 67 -3.63 9.023 -4.2 -22.8 31.6 Week 130 70 69.71 29.949 66.9 14.7 130.5 (44.2; 90.4) 70 -6.72 10.036 -4.8 -28.0 16.8 Week 156 69 69.35 31.025 67.3 13.4 138.6 (44.8; 91.3) 69 -7.43 8.525 -7.8 -25.5 10.8 Week 160 60 66.25 30.315 67.3 12.7 125.6 (42.3; 91.6) 60 -8.12 11.239 -7.0 -34.3 13.0

Prescribed water intake Baseline 91 77.65 24.838 79.0 30.8 125.6 (58.2; 96.9) Week 3 74 75.36 25.666 70.9 29.5 126.0 (57.1; 96.2) 74 -0.36 7.304 0.0 -23.3 15.1 Week 6 78 75.56 25.263 77.0 29.3 124.3 (53.5; 97.7) 77 -0.36 7.794 -0.4 -18.3 24.8 Week 12 70 74.15 26.770 74.1 28.6 127.4 (53.7; 90.6) 70 -1.29 7.719 -0.8 -24.7 20.7 Week 26 74 76.43 27.497 74.4 29.1 131.5 (55.0; 98.3) 74 -0.56 7.316 -1.0 -16.5 27.0 Week 36 64 72.18 27.451 68.6 25.8 127.4 (52.7; 96.8) 64 -2.19 8.123 -2.6 -22.3 24.8 Week 52 64 73.19 26.524 71.4 23.1 129.2 (54.8; 95.7) 63 -2.89 8.316 -3.9 -23.3 22.9 Week 78 68 74.70 27.771 72.4 18.9 127.4 (56.6; 95.1) 68 -2.38 8.699 -2.5 -18.9 24.8 Week 104 65 70.42 29.545 72.6 15.5 131.5 (42.2; 92.9) 65 -5.54 10.797 -5.2 -38.4 23.8 Week 130 64 67.21 29.189 64.7 11.9 131.5 (41.4; 91.8) 64 -5.70 10.779 -5.1 -44.8 25.6 Week 156 70 70.24 29.405 68.2 9.7 127.4 (44.8; 90.6) 69 -6.84 11.619 -6.7 -41.2 24.8 Week 160 55 64.75 29.423 63.3 8.1 117.0 (40.3; 88.0) 55 -8.51 12.893 -8.8 -44.8 35.7

29

Table S15. Mixed model with repeated measures for resting mean arterial pressure (MAP) from week 0 to week 156

*Weeks 0, 26, 52, 78, 104, 130, and 156 combined. No imputation of missing data was performed. Results are from a mixed model with repeated measures, with MAP over time (Weeks 0, 26, 52, 78, 104, 130, and 156) as the dependent variable; and the independent variables: baseline Mayo Clinic Imaging Subclass 1B-1E, baseline eGFR stratification category (<60 or ≥60 mL/min/1.73m2), baseline log 10 Ht-TKV, baseline 24-hour urine osmolality, treatment group, visit, and treatment*visit interaction. An unstructured variance-covariance matrix was used. LS, least squares; SE, standard error

Visit Mean Arterial Pressure

ad libitum water intake (N=92)


(N=92) Overall*

LS Mean (SE) 99.3 (1.0) 98.6 (1.0) LS Mean Difference (SE): Prescribed minus ad libitum -0.7 (1.2) 95% Confidence Interval for Treatment Difference (-3.1,1.6) P-value for Treatment Difference 0.540 P-value for Visit 0.054 P-value for Treatment by Visit Interaction 0.589

Week 0

LS Mean (SE) 98.9 (1.2) 96.9 (1.2) LS Mean Difference (SE): Prescribed minus ad libitum -2.0 (1.5) 95% Confidence Interval for Treatment Difference (-4.9,1.0) P-value for Treatment Difference 0.193

Week 26


Week 52


Week 78

LS Mean (SE) 99.1 (1.2) 99.9 (1.2) LS Mean Difference (SE): Prescribed minus ad libitum 0.8 (1.5) 95% Confidence Interval for Treatment Difference (-2.1,3.7) P-value for Treatment Difference 0.585

Week 104


Week 130


Week 156

LS Mean (SE) 100.1 (1.4) 100.8 (1.4) LS Mean Difference (SE): Prescribed minus ad libitum 0.7 (1.8) 95% Confidence Interval for Treatment Difference (-2.9,4.3) P-value for Treatment Difference 0.698

30

Table S16. Summary of systolic blood pressure over time

Systolic blood pressure (mmHg) Change from Baseline Group Scheduled Visit n Mean SD Min. Median Max. IQR n Mean SD Min. Median Max. ad libitum water intake Screening 92 133.4 13.10 100.3 133.2 168.3 (123.2; 144.7)

Baseline 91 130.8 13.13 100.0 131.3 161.0 (120.7; 140.0) Week 26 82 132.5 14.94 104.7 132.5 173.3 (121.0; 142.3) 82 1.95 13.48 -35.0 2.00 41.3 Week 52 77 131.7 13.32 104.0 132.0 163.7 (123.7; 141.7) 77 1.57 12.35 -23.7 2.00 30.3 Week 78 75 132.3 11.48 105.7 131.0 159.0 (124.7; 140.0) 75 1.36 12.51 -35.0 1.40 29.7 Week 104 58 131.5 14.94 98.7 132.0 172.3 (121.3; 140.3) 58 1.16 14.16 -28.7 1.70 43.3 Week 130 63 131.8 13.86 111.0 129.7 172.7 (122.0; 141.3) 63 -0.03 14.42 -37.3 0.30 34.0 Week 156 74 131.5 16.30 95.7 129.7 178.7 (119.0; 141.0) 74 1.54 16.34 -44.3 2.70 39.0

Prescribed water intake Screening 92 129.9 12.72 101.3 131.2 159.7 (120.7; 138.9) Baseline 89 129.5 11.92 102.3 128.3 161.7 (121.0; 136.0) Week 26 77 130.8 13.31 105.7 129.7 173.0 (121.3; 138.7) 76 0.39 11.37 -25.3 -0.50 33.7 Week 52 70 129.7 13.46 103.0 127.3 163.3 (120.3; 137.3) 68 -0.19 12.24 -23.3 -0.35 44.6 Week 78 75 133.2 15.12 105.7 131.0 182.3 (123.0; 140.3) 73 3.73 14.22 -27.7 2.00 36.0 Week 104 51 130.3 11.22 109.3 129.0 164.0 (121.3; 138.3) 49 0.86 9.56 -20.0 1.30 19.4 Week 130 54 129.8 15.29 99.7 128.7 182.7 (120.3; 138.0) 52 -0.50 15.75 -36.3 -0.00 44.4 Week 156 71 132.9 15.22 104.7 134.3 181.3 (121.7; 141.0) 70 3.90 13.80 -28.3 1.85 43.0

31

Table S17. Summary of diastolic blood pressure over time

Diastolic blood pressure (mmHg) Change from Baseline Group Scheduled Visit n Mean SD Min. Median Max. IQR n Mean SD Min. Median Max. ad libitum water intake Screening 92 83.69 10.19 61.7 83.15 108.0 (76.2; 89.0)

Baseline 91 82.71 10.69 55.3 81.00 110.3 (75.3; 89.3) Week 26 82 82.48 10.66 57.7 81.70 106.3 (75.0; 91.3) 82 -0.17 9.30 -21.0 -0.85 28.3 Week 52 77 82.59 9.45 65.0 82.70 107.3 (77.0; 88.3) 77 0.55 8.81 -28.0 1.30 20.7 Week 78 75 81.73 7.46 63.3 82.00 99.3 (76.7; 87.0) 75 -0.49 9.36 -20.0 0.30 17.0 Week 104 58 82.68 11.44 63.3 82.50 129.0 (75.0; 87.7) 58 1.35 11.76 -23.7 0.50 51.0 Week 130 63 81.40 9.74 62.0 81.30 104.7 (74.7; 87.3) 63 -0.97 10.43 -24.6 -2.00 24.0 Week 156 74 82.84 10.50 60.7 81.70 109.3 (75.0; 88.7) 74 1.46 10.78 -30.7 1.85 26.0

Prescribed water intake Screening 92 82.31 10.01 61.0 81.30 104.7 (75.5; 90.2) Baseline 89 80.29 10.44 59.0 80.70 103.0 (72.7; 88.3) Week 26 77 82.26 9.43 62.0 83.30 107.3 (75.3; 87.7) 76 1.61 8.62 -20.3 2.55 20.6 Week 52 70 81.92 10.89 57.0 82.15 107.3 (73.3; 90.3) 68 2.14 8.39 -14.0 2.00 27.3 Week 78 75 83.01 9.89 61.3 82.30 107.3 (76.0; 90.3) 73 3.46 9.39 -16.0 3.00 26.6 Week 104 51 82.29 8.56 63.7 81.70 101.0 (75.3; 89.7) 49 4.31 8.06 -16.0 4.00 29.3 Week 130 54 80.56 9.29 53.7 80.00 100.0 (75.3; 87.7) 52 1.12 12.01 -30.0 2.00 33.0 Week 156 71 84.49 10.48 58.0 83.70 114.0 (77.0; 92.3) 70 4.73 10.41 -23.0 3.85 32.3

32

Table S18. Mixed model with repeated measures for urine albumin to creatinine ratio (mg/g) from week

0 to week 156

Visit Urine Albumin to Creatinine Ratio (mg/mmol)

ad libitum

water intake

(N=92)

Prescribed

water intake

(N=92)

Overall*

LS Mean (SE) 90.08 (10.12) 74.69 (10.18)

LS Mean Difference (SE) -15.39 (12.00)

95% Confidence Interval for Treatment Difference (-39.03,8.240)

P-value for Treatment Difference 0.201

P-value for Visit 0.023

P-value for Treatment by Visit Interaction 0.123

Week 0

LS Mean (SE) 62.43 (14.06) 65.27 (14.18)

LS Mean Difference (SE) 2.84 (18.35)

95% Confidence Interval for Treatment Difference (-33.18, 38.87)


Week 12

LS Mean (SE) 70.32 (14.4) 87.43 (14.49)

LS Mean Difference (SE) 17.12 (18.86)



Week 26

LS Mean (SE) 68.54 (14.52) 62.93 (15.07)




Week 36

LS Mean (SE) 80.82 (14.94) 77.77 (15.25)




Week 52

LS Mean (SE) 99.82 (14.86) 60.33 (15.2)


95% Confidence Interval for Treatment Difference (-78.3, -0.73)


Week 78

LS Mean (SE) 97.12 (14.74) 66.03 (14.98)




Week 104

LS Mean (SE) 93.73 (15.09) 72.29 (15.24)




Week 130

LS Mean (SE) 124.2 (15.2) 77.51 (15.25)


95% Confidence Interval for Treatment Difference (-85.99, -7.39)


Week 156

LS Mean (SE) 113.74 (15.42) 102.62 (15.1)



P-value for Treatment Difference 0.580 *Weeks 0, 12, 26, 36, 52, 78, 104, 130, and 156 combined. No imputation of missing data was performed. Results are from a mixed model with repeated measures, with Urine Albumin to Creatinine Ratio over time (Weeks 0, 12, 26, 36, 52, 78, 104, 130, and 156) as the dependent variable; and the independent variables: baseline Mayo Clinic Imaging Subclass 1B-1E, baseline eGFR stratification category (<60 or ≥60 mL/min/1.73m2), baseline log 10 Ht-TKV, baseline 24-hour urine osmolality, treatment group, visit, and treatment*visit interaction. An autoregressive model (AR) variance-covariance matrix was used. LS Mean Difference = LS mean of prescribed water intake – LS mean of ad libitum water intake. LS, least squares; SE, standard error.

33

Table S19. Summary of urine albumin to creatinine ratio (mg/g) over time from baseline to week 156

Albumin/Creatinine Ratio (mg/g)

Actual Values Change From Screening 2 Group Scheduled Visit n Mean SD Min. Median Max. IQR n Mean SD Min. Median Max.


Baseline/Screening 1 90 45.84 70.18 3.54 23.89 512.39 (13.27; 48.67) Baseline/Screening 2 82 43.01 61.06 2.65 20.35 289.38 (11.50; 42.48) Baseline/Screening* 91 44.96 58.32 3.54 23.01 286.73 (11.50; 52.21)

Week 12 72 50.09 83.72 5.31 23.89 519.47 (12.39; 44.25) 65 7.88 48.85 -158.41 1.77 253.10 Week 26 72 47.70 69.91 3.54 25.58 352.21 (11.50; 40.71) 65 1.86 44.34 -257.52 0.00 110.62 Week 36 65 58.94 111.06 3.54 22.12 628.32 (13.27; 41.59) 58 11.86 75.04 -267.26 1.42 357.52 Week 52 68 83.19 207.26 2.65 23.10 1230.97 (10.62; 56.64) 62 40.35 170.88 -236.28 1.68 960.18 Week 78 72 69.29 131.68 3.54 24.96 882.30 (11.50; 70.80) 66 28.94 103.10 -239.82 2.57 611.50 Week 104 66 73.89 148.76 2.65 26.02 879.65 (10.62; 53.10) 61 26.02 107.52 -251.33 2.65 613.27 Week 130 66 103.10 195.93 3.54 34.07 1246.02 (16.81; 89.38) 62 54.96 168.41 -255.75 7.61 975.22 Week 156 65 91.15 156.99 3.54 36.02 1007.08 (15.93; 67.26) 61 47.35 133.54 -231.86 9.65 766.37


Baseline/Screening 1 91 59.12 168.76 4.42 18.58 1396.46 (9.73; 49.56) Baseline/Screening 2 81 46.02 81.86 2.65 19.47 486.73 (9.73; 42.48) Baseline/Screening* 92 50.97 116.73 4.42 19.03 900.88 (9.73; 46.02)

Week 12 71 65.13 172.83 3.54 22.12 1330.09 (11.50; 47.79) 63 25.93 166.19 -151.33 2.65 1298.23 Week 26 62 39.73 57.43 4.42 15.49 353.98 (9.73; 44.25) 59 2.12 22.39 -50.44 0.88 100.00 Week 36 61 48.67 123.01 5.31 17.52 935.40 (9.73; 38.94) 54 14.69 76.28 -46.02 0.44 530.97 Week 52 63 38.94 53.63 4.42 15.93 274.34 (8.85; 43.36) 55 0.71 41.06 -176.11 0.71 123.01 Week 78 69 46.02 70.71 0.88 19.20 346.90 (8.85; 38.94) 60 2.83 60.80 -262.83 -0.53 204.42 Week 104 65 52.92 103.10 1.77 17.17 542.48 (11.50; 38.94) 58 10.53 58.32 -69.91 0.00 358.41 Week 130 65 61.42 116.46 1.77 22.39 780.53 (13.27; 53.10) 57 16.46 104.51 -257.52 2.12 596.46 Week 156 70 82.21 173.72 1.77 31.24 1217.70 (14.16; 60.18) 59 40.71 164.69 -243.36 0.71 116.8

*Mean of Baseline/Screening 1 and Baseline/Screening 2 values

34

Table S20. Mixed model with repeated measures for kidney pain from screening to week 156

Visit Kidney Pain


(N=92)


(N=92) Overall*

LS Mean (SE) 0.5 (0.1) 0.4 (0.1) LS Mean Difference (SE) -0.1 (0.1) 95% Confidence Interval for Treatment Difference (-0.3,0.0) P-value for Treatment Difference 0.069 P-value for Visit 0.628 P-value for Treatment by Visit Interaction 0.176

Week 0


Week 26


Week 52


Week 78


Week 104


-0.1 (0.1)


Week 130


Week 156


*Weeks 0, 26, 52, 78, 104, 130, and 156 combined. No imputation of missing data was performed. Results are from a mixed model with repeated measures, with kidney pain over time (Weeks 0, 26, 52, 78, 104, 130, and 156) as the dependent variable; and the independent variables: baseline Mayo Clinic Imaging Subclass 1B-1E, baseline eGFR stratification category (<60 or ≥60 mL/min/1.73m2), baseline log 10 Ht-TKV, baseline 24-hour urine osmolality, treatment group, visit, and treatment*visit interaction. An unstructured variance-covariance matrix was used. LS Mean Difference = LS mean of prescribed water intake – LS mean of ad libitum water intake. LS, least squares; SE, standard error

35

Table S21. Categorical summary of kidney pain over time

Grantham PKD Pain Scale (developed by Dr. J. Grantham): *0 = No pain; 1 = Noticeable but not distracting pain; 2 = Pain requiring over the counter analgesics; 3 = Pain requiring a doctor’s visit; 4 = Pain requiring narcotics; 5 = Pain requiring hospital admission. For repeated assessments in a scheduled visit, the worst (highest) kidney pain category was used. Denominator for percentages is the number of patients in the respective treatment group.

Visit ad libitum water intake (N=92) Kidney pain category*

Prescribed water intake (N=92) Kidney pain category*

0 1 2 3 4 5 0 1 2 3 4 5 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Baseline 38 41.3 42 45.7 9 9.8 1 1.1 0 0.0 1 1.1 53 57.6 29 31.5 7 7.6 0 0.0 0 0.0 1 1.1 Week 1 60 65.2 24 26.1 6 6.5 2 2.2 0 0.0 0 0.0 60 65.2 26 28.3 5 5.4 0 0.0 0 0.0 0 0.0 Week 26 52 56.5 23 25.0 9 9.8 0 0.0 0 0.0 0 0.0 55 59.8 15 16.3 6 6.5 4 4.3 0 0.0 0 0.0 Week 52 43 46.7 24 26.1 8 8.7 0 0.0 0 0.0 1 1.1 49 53.3 19 20.7 2 2.2 1 1.1 0 0.0 0 0.0 Week 78 44 47.8 25 27.2 8 8.7 1 1.1 0 0.0 0 0.0 59 64.1 13 14.1 1 1.1 2 2.2 1 1.1 0 0.0 Week 104 44 47.8 27 29.3 2 2.2 1 1.1 0 0.0 1 1.1 46 50.0 16 17.4 2 2.2 1 1.1 0 0.0 1 1.1 Week 130 54 58.7 16 17.4 4 4.3 0 0.0 1 1.1 0 0.0 50 54.3 16 17.4 3 3.3 1 1.1 0 0.0 0 0.0 Week 156 53 57.6 16 17.4 6 6.5 1 1.1 1 1.1 1 1.1 59 64.1 16 17.4 1 1.1 0 0.0 0 0.0 0 0.0

36

Table S22. Proportion of patients from prescribed water intake group reporting acceptability of life-long prescription

Visit Yes No Not done

n (%) n (%) n (%) Week 26 64 80.0 7 8.8 9 11.3 Week 52 51 68.9 10 13.5 13 17.6 Week 78 53 68.8 9 11.7 15 19.5 Week 104 48 70.6 13 19.1 7 10.3 Week 130 49 66.2 17 23.0 8 10.8 Week 156 56 72.7 16 20.8 5 6.5

n, number of patients; Yes = water prescription acceptable life-long; No = water prescription not acceptable life-long; Not done = participants without response

37

Table S23. Summary of serum sodium (mmol/L) over time

Serum sodium (mmol/L)

Actual Values Change from Screening Group Scheduled Visit n Mean SD Median Min Max IQR n Mean SD Median Min Max

ad libitum water intake (N=92)

Screening/Baseline 92 139.59 1.756 139.5 135.0 144.5 (138.5; 141.0) Week 12 76 139.63 2.238 140.0 134.0 145.0 (138.0; 141.0) 76 0.01 1.748 -0.5 -3.5 4.0 Week 26 78 139.46 1.959 140.0 135.0 144.0 (138.0; 141.0) 78 -0.12 1.821 0.0 -6.5 3.5 Week 36 71 139.52 1.948 139.0 136.0 146.0 (138.0; 141.0) 71 0.08 1.677 0.0 -3.5 4.0 Week 52 72 139.78 2.357 140.0 134.0 146.0 (138.5; 141.0) 72 0.17 1.854 0.0 -3.5 5.0 Week 78 78 139.86 2.050 140.0 134.0 145.0 (139.0; 141.0) 78 0.35 2.172 0.5 -6.0 5.5 Week 104 68 139.91 2.399 140.0 133.0 147.0 (139.0; 141.0) 68 0.31 2.582 0.0 -6.0 11.0 Week 130 70 139.61 2.324 140.0 131.0 144.0 (138.0; 141.0) 70 -0.01 1.940 0.0 -4.5 5.0 Week 156 69 139.49 2.501 139.0 128.0 145.0 (138.0; 141.0) 69 -0.03 2.226 0.0 -10.5 4.5 Week 160 60 139.57 2.189 140.0 132.0 146.0 (138.0; 141.0) 60 -0.04 1.833 0.0 -4.0 3.5

Prescribed fluid intake (N=92)

Screening/Baseline 91 139.90 1.770 140.0 135.0 143.5 (139.0; 141.0) Week 3 74 139.30 2.642 139.0 125.0 143.0 (138.0; 141.0) 74 -0.66 2.238 -0.5 -10.0 4.5 Week 6 78 139.54 2.666 140.0 131.0 145.0 (138.0; 141.0) 77 -0.40 2.122 0.0 -5.5 4.5 Week 12 70 139.41 2.387 139.0 136.0 145.0 (138.0; 141.0) 70 -0.58 2.088 -0.5 -6.5 5.0 Week 26 74 139.47 2.210 140.0 133.0 146.0 (138.0; 140.0) 74 -0.55 2.082 -0.5 -5.5 5.0 Week 36 64 139.03 2.637 139.0 131.0 145.0 (138.0; 141.0) 64 -1.06 2.371 -1.5 -6.0 6.0 Week 52 64 139.67 2.545 140.0 134.0 147.0 (138.0; 141.0) 63 -0.39 2.575 -0.5 -6.0 8.0 Week 78 68 139.44 2.147 139.5 133.0 144.0 (138.0; 141.0) 68 -0.40 1.874 -0.5 -6.5 3.5 Week 104 65 139.57 2.114 140.0 135.0 148.0 (138.0; 141.0) 65 -0.38 2.055 -0.5 -5.0 5.5 Week 130 64 139.16 2.276 139.0 133.0 143.0 (138.0; 141.0) 64 -0.81 2.253 -1.0 -7.0 4.0 Week 156 70 139.33 2.501 140.0 130.0 145.0 (138.0; 141.0) 69 -0.49 2.119 -0.5 -5.0 5.0 Week 160 55 139.35 2.489 140.0 131.0 144.0 (138.0; 141.0) 55 -0.55 2.123 -0.5 -7.0 3.5

38

Table S24. Adverse events by organ group

Organ group ad libitum water intake (N=92)

No. of patients that experienced at least

one AE1

Prescribed water intake (N=92)

No. of patients that experienced at least

one AE1 Blood and lymphatic system disorders 7 2 Cardiac disorders 6 12 Congenital, familial, and genetic disorders 3 2 Ear and labyrinth disorders 3 3 Endocrine disorders 2 3 Eye disorders 8 12 Gastrointestinal disorders 54 38 General disorders 21 35 Hepatobiliary disorders 12 7 Immune system disorders 2 2 Infections and infestations 71 63 Injury, poisoning and procedural complications 25 16 Investigations 10 11 Metabolism and nutrition disorders 30 33 Musculoskeletal and connective tissue disorders 48 44 Neoplasms benign, malignant, and unspecified 2 5 Nervous system disorders 24 18 Pregnancy, puerperium, and perinatal conditions 4 3 Psychiatric disorders 10 12 Kidney and urinary disorders 31 32 Reproductive system and breast disorders 7 2 Respiratory, thoracic and mediastinal disorders 14 17 Skin and subcutaneous tissue disorders 13 12 Vascular disorders 42 36

1 An adverse event (AE) is any untoward medical occurrence, unfavourable and unintended sign, symptoms or disease in the participant temporarily associated with the clinical study whether or not considered related to the procedures. AEs were documented from the time of randomization until the final visit.

39

Table S25. Adverse events1 ranked by highest number of events to lowest

1Only adverse events with a total of ≥10 events included URTI, upper respiratory tract infection UTI, urinary tract infection.

Event Number of Events

% Total Events (N=1507)

URTI 195 12.9 Hypertension 110 7.3 Flank pain 39 2.6 Back pain 38 2.5 UTI 38 2.5 Gastroenteritis 37 2.5 Haematuria 33 2.2 Abdominal Pain 31 2.1 Fatigue 23 1.5 Hyponatremia 20 1.3 Abdominal Distension 19 1.3 Kidney Impairment 18 1.2 Headache 18 1.2 Arthralgia 18 1.2 Hypercholesterolaemia 18 1.2 Iron Deficiency 16 1.1 Dizziness 15 1.0 Gout 15 1.0 Peripheral Oedema 15 1.0 Nausea 15 1.0 Dysuria 14 0.9 Gastroesophageal reflux disease 14 0.9 Kidney pain 13 0.9 Pruritis 12 0.8 Sinusitis 12 0.8 Muscle spasms 11 0.7 Hepatic Cyst 10 0.7

40

Table S26. Adverse events by treatment group

Event ad libitum water intake

(N=92)

No. of patients


(N=92)

No. of patients Adverse events more common in Prescribed fluid intake group1,2,3

Flank pain 15 16 Fatigue 8 15 Haematuria 7 14 Urinary tract infection 10 13 Nausea 5 10 Abdominal distension 7 8 Dizziness 7 8 Hyponatremia 2 8 Kidney impairment 6 8 Cough 2 6 Gout 3 6 Chest pain 1 5 Dyspnea 2 5 Vitamin D Deficiency 3 5 Kidney cyst rupture 2 5

Adverse events more common in ad libitum fluid intake group1,2,3

Hypertension4 41 34 Gastroenteritis 18 14 Abdominal pain 16 10 Arthralgia 11 6 Headache 10 6 Hypercholesterolaemia 10 8 Iron Deficiency 10 4 Edema (Peripheral) 8 4 Dysuria 7 6 Gastroesophageal reflux disease 7 6

Hepatic Cysts 6 4 Nephrolithiasis 6 2 Hemorrhoids 5 0 Pancreatic Cyst 5 2 Pruritis 5 4 Sinusitis 5 3

1 Only adverse events experienced by ≥5% of either group were included. 2 Adverse events were categorized according to the Medical Dictionary for Regulatory Activities (MedDRA). 3 An AE is any untoward medical occurrence, unfavorable and unintended sign, symptoms, or disease in the participant temporarily associated with the clinical study whether or not considered related to the procedures. AEs will be documented from the time of randomization until the final visit. 4 Includes episodes of worsening hypertension

41

Table S27. Serious adverse events by treatment group

1 Only serious adverse events experienced by ≥2% of either group were included 2 A serious adverse event is defined as an adverse event that result in the following outcomes is considered as serious:

a. Death b. Life-threatening c. Requires in-patient hospitalization OR significant testing or treatment upon presentation to ED OR if

ambulance is called by participant i. Significant testing or treatment beyond triage, beyond pain relief or prescription given (e.g.

given intravenous antibiotics or pain relief or fluids OR CT scan/other imaging) ii. Please note, the AE or AEs that prompted presentation to the hospital should only be labelled

serious. E.g. if participant has cough and then develops macro-haematuria and fever, presents to the emergency department because of macro-haematuria and fever, then only these should be marked as serious despite concomitant cough.

iii. Excludes expected or planned pregnancy and caesarean sections d. Significant disability or incapacity e. Congenital abnormality or birth defect f. Medically significant

i. Hyponatremia ii. Hypernatremia

iii. Kidney failure iv. Doubling of serum creatinine from baseline (Visit 2) v. Significant drop in kidney function (~25% or greater change in eGFR or serum creatinine

between two subsequent visits) 3 No SAEs were life-threatening or resulted in death, significant disability or incapacity or congenital abnormality or birth defect as per a, b, d, e above.

Serious Adverse Event (SAE)1,2,3 ad libitum water intake

(N=92)

No. of patients that experienced at least one

SAE


(N=92)

No. of patients that experienced at least one

SAE Total 23 37 Hyponatremia

Mild (130-135mmol/L) Moderate (125-129mmol/L) Severe (<125mmol/L)

Hypernatremia

2 0 0 1

7 1 0 3

Kidney Complications Significant decline in kidney function (>25% eGFR) Doubling of serum creatinine from baseline End-stage kidney failure

6 3 2

8 4 2

Cardiovascular complications Chest pain Preeclampsia

0 1

3 2

Systemic complications Abdominal hernia

2

0

Other Headache Nausea Gastroenteritis Pneumonia Dyspnoea

0 0 2 2 2

2 2 1 1 1

42

References

1. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant

polycystic kidney disease. N Engl J Med 2012;367:2407-18.

2. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J

Am Soc Nephrol 2009;20:205-12.

3. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of autosomal dominant

polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol

2015;26:160-72.

4. Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal

dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012;7:479-86.

5. Cline MG, Meredith KE, Boyer JT, Burrows B. Decline of height with age in adults in a general

population sample: estimating maximum height and distinguishing birth cohort effects from actual loss

of stature with aging. Hum Biol 1989;61:415-25.

6. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging Classification of Autosomal Dominant

Polycystic Kidney Disease: A Simple Model for Selecting Patients for Clinical Trials. Journal of the

American Society of Nephrology 2015;26:160.

7. Wang CJ, Creed C, Winklhofer FT, Grantham JJ. Water prescription in autosomal dominant

polycystic kidney disease: a pilot study. Clin J Am Soc Nephrol 2011;6:192-7.

8. Wang CJ, Grantham JJ, Wetmore JB. The medicinal use of water in renal disease. Kidney Int

2013;84:45-53.

9. Proceedings of the Australasian Association of Clinical Biochemists’ 57(th) Annual Scientific

Conference. Clin Biochem Rev 2019;40:S1-S48.

10. Nagao S, Nishii K, Katsuyama M, et al. Increased water intake decreases progression of

polycystic kidney disease in the PCK rat. J Am Soc Nephrol 2006;17:2220-7.

11. Wang X, Gattone V, 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor

antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J

Am Soc Nephrol 2005;16:846-51.

43

Additional Acknowledgements Staff at the McCloud Consulting Group (Sydney, Australia) – the authors thank Julie Hill (Statistician) (who prepared the first version of the statistical analysis plan), Peter Button (Statistician) (for assistance with additional analyses) and Nam Truong (data management).

Staff at the Australasian Kidney Trials Network (Brisbane, Australia) – the authors thank Laura Robison (Clinical Project Manager), Donna Reidlinger (Clinical Operations Manager) and Alicia Morrish, who provided support with trial oversight and monitoring.

Data Safety Monitoring Board (DSMB) – the authors thank member of the DSMB for generously providing their time and expertise in overseeing this trial. The Board consisted of Professor Peter Kerr (Chair, Monash Medical Centre, Melbourne, Australia), Dr Jessica Ryan (Monash Medical Centre, Melbourne, Australia), Professor Ben Cowley (College of Medicine, The University of Oklahoma) and Professor Val Gebski (The University of Sydney).

PKD Australia – the authors are grateful to Robert Gardos, Charmaine Green, Ian Cornell and Judith Cornell for their support, collaboration and encouragement to conduct this study.

Professor Jeremy Chapman (previous Head of Department of Renal Medicine, Westmead Hospital). The first author is grateful to Professor Chapman for providing Departmental resources and encouragement to undertake this study.

Human Research Ethics/Governance and Clinical Trial Support Staff at all study sites Westmead Hospital, Sydney, NSW Westmead Institute for Medical Research, Sydney, NSW Nepean Hospital, Sydney, NSW Liverpool Hospital, Sydney, NSW

Norwest Private Hospital, Sydney, NSW Gosford Renal Research, Gosford, NSW Gosford Nephrology, Gosford, NSW Nephrology at The Mater, Sydney, NSW John Hunter Hospital, Newcastle, NSW St. George Hospital, Sydney, NSW Prince of Wales Hospital, Sydney, NSW Wollongong Hospital, Wollongong, NSW Sir Charles Gardiner Hospital and the Harry Perkins Institute for Medical Research, Perth, Western Australia Princess Alexandra Hospital, Queensland Staff who assisted with MRI acquisition and image quality at the following MRI sites Castlereagh Imaging, 20-22 Mons Road, Westmead NSW 2145 Castlereagh Imaging, Suite 4, 68 Derby Street, Kingswood NSW 2747

44

Dr. Glenn and Partners, g01/360-364 Crown Street, Wollongong NSW 2500 I-Med Radiology (Formerly Insight Imaging), 151 Walcott Street, Mount Lawley WA 6050 Mater Imaging, LG Floor Mater Hospital, 25 Rocklands Road, Wollstonecraft NSW 2065 Nepean Hospital, Derby Street, Kingswood NSW 2747 Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba QLD 4102 PRP Imaging, William Street, Gosford NSW 2250 PRP Imaging, 11 Norbrik Drive, Bella Vista NSW 2153 Spectrum Imaging, Wales Medical Centre, Level 1/66 High Street, Randwick NSW 2031 Spectrum Imaging, 171 Bigge St, Liverpool NSW 2170 Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145 Staff who assisted with blood and urine collections and analyses at the pathology centres Barrett & Smith Pathology, 31 Lawson Street, Penrith 2750 NSW Bathurst Base Hospital, Pathology Collection Rooms, 199 Russell Street, Bathurst 2795 NSW CliniPath, 310 Selby St North, Osborne Park WA 6017 Clinical Labs, 23 Walters Drive, Osborne Park WA 6017 Clinpath Pathology, 21 James Congdon Drive, Mile End SA 5031 Douglass Hanly Moir, 14 Giffnock Avenue, Macquarie Park, NSW 2113 Laverty, 60 Waterloo Road, Macquarie Park NSW 2113; Pathology North, Belmont District Hospital, Croudace Bay Road, Belmont NSW 2280 PathWest, Locked Bag 2009, Nedlands, WA, 6909 Princess Alexandra Hospital Laboratory, Ipswich Road, Woolloongabba Qld 4102; QML, 11 Riverview Place, Metroplex on Gateway Murarrie QLD 4172; Southern Pathology, Locked Bag 35, Wollongong NSW 2500 Sullivan Nicolaides Pathology, 24 Hurworth St, Bowen Hills, QLD 4006 Westmead Hospital ICPMR, Corner Darcy and Hawkesbury Rd, Level 2, University Clinic- Outpatient Department, Westmead NSW, Australia 2145

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