clinical trials in hypertension
TRANSCRIPT
CLINICAL TRIALS IN HYPERTENSION
NIDHI SHARMA15CRM2268
Hypertension (HTN) is a major public health concern, affecting 26% of adults worldwide
People with HTNworldwide in 2000972 million
Increase in the number of adults with HTN globally by 2025
60%
Percentage of all global healthcare spending
attributable to treat high blood pressure
10%
Annual worldwide cost of treating hypertension$370 billion
1.6 Billion HTN patients estimated
by 2025
INTRODUCTION
Increase of cardiovascular risk with increasing levels of blood pressure
The higher the blood pressure,higher the risk of both stroke and coronary events
Nonfatal and fatal CVS diseases increase progressively with higher levels of both SBP & DBP
Elevation in SBP more imp than DBP not only for diagnosis and therapy but also for prognosis
The dividing line between normotension and hypertension is arbitrary and vary with age(current definition)
GUIDELINES OF HTN
CLASSIFICATION OF HYPERTENSION
May be classified according to-
Aetiology: essential or primary hypertension vs. secondary hypertension
Severity: according to WHO/ISH, JNC 7, or ESC/ESH guidelines
Type: systolic, diastolic or both;
Effects of treatment
Blood Pressure (mmHg)Grade 3 HTSBP ≥180or DBP ≥110
Grade 2 HTSBP 160–179or DBP 100–109
Grade 1 HTSBP 140–159or DBP 90–99
High normalSBP 130–139or DBP 85–89
Other risk factors,asymptomatic organ damage or disease
No other RF1-2 RF≥3 RF
OD, CKD stage 3 or diabetes
Symptomatic CVD, CKD stage ≥4 or
diabetes with OD/RFs
Total CV RISK
Blood Pressure (mmHg)Grade 3 HTSBP ≥180or DBP ≥110
Grade 2 HTSBP 160–179or DBP 100–109
Grade 1 HTSBP 140–159or DBP 90–99
High normalSBP 130–139or DBP 85–89
Other risk factors,asymptomatic organ damageor disease
No other RF1-2 RF≥3 RF
OD, CKD stage 3 or diabetes
Symptomatic CVD, CKD stage ≥4 or
diabetes with OD/RFs
Compelling in
dications
No Compelling indications
CHOICE OF DRUG TREATMENT
The A,B,C,D drug classes
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Beta-blockers
Calcium channel blockers
Diuretics
Possible combinations of classes of antihypertensive drugs
D
A
A
C
B
NOT JUST JNC VII “RENOVATED” BUT DEMOLISHED AND RECONSTRUCTED.
11977
21980
31984
41988
51993
61997
72003
82014
The Joint National Committee (JNC )
JNC 8..?THE EVIDENCE BASED GUIDELINES
Rigorous,evidence based approach to recommend treatment
thresholds,
goals, and medications in the management of HTN in adults.
Evidence was from RCTs,the gold standard for determining efficacy
and effectiveness.
This JNC 8 guideline has not redefined high BP, and considers the 140/90 mm Hg definition from JNC 7 reasonable.
Category SBP (mm Hg) DBP (mm Hg)
Normal < 120 < 80
Pre – hypertension 120-139 80-90
HypertensionStage 1 140 – 159 90 – 99
Stage 2 160 and above 100 and above
DMCKD
C D A
B
A C DAlone or in combination
Alone or in combination with other drug class
JNC 7 Compelling Indications
Questions guiding the JNC 8 review
The answers to these three questions are reflected in 9 recommendations
When to begin treatment, how low to aim for, and which antihypertensivemedications to use.
Goal BP evidence statement is from…
HYVET
Syst-Eur (The Systolic Hypertension in Europe Trial)
SHEP(Systolic Hypertension in the Elderly Program)
JATOS (Japanese Trial to assess Optimal Systolic blood pressure in elderly hypertensive patients)
VALISH (VALsartan in elderly Isolated Systolic Hypertension Study)
CARDIO-SIS
High risk groups
Black persons
Those with CVD including stroke
Multiple risk factors
Recommendation (Strong)
Recommendation (Strong)
Recommendation (Expert)
General population ≥60 years
SBP ≥150 mm Hgor DBP ≥90 mm Hg
SBP <150 mm Hgand DBP <90 mm Hg
General population <60 years DBP ≥90 mm Hg
DBP <90 mm Hg
General population <60 years
SBP ≥140 mm Hg SBP <140 mm Hg
RecommendationsGoalsBP thresholds
Recommendation 4(expert)
Recommendation (expert)
Recommendation 6 (Moderate recommendation)
Population with CKD ≥18 years SBP ≥140 mm Hgor DBP ≥90 mm Hg
SBP <140 mm Hgand DBP <90 mm Hg
Population with diabetes ≥18 yearsSBP ≥140 mm Hg
or DBP ≥90 mm Hg SBP <140 mm Hgand DBP <90 mm Hg
General nonblack population ( ± diabetes )
or
RecommendationsGoalsBP thresholds
Initial treatment
A C Dor
RecommendationsRecommendation 7 (Moderate)
Recommendation 8(Moderate)
Recommendation 9(Expert)
General ( ± diabetes ) black population
or
Population with CKD ≥18 years(irrespective of race or diabetes)
Goal BP not reachedwithin a month of treatment Increase the dose of the initial drug,
or add a second drug (from the list provided)
Goal BP not reachedwith 2 drugs
Add and titrate a third drug (from the list provided)Do not use an ACEI and an ARB together in the same patient
Initial treatments
Initial or add-on treatments
Non control strategies
C D
A
CONT
JNC 7 vs JNC 8: Methodology
JNC 7
Nonsystematic literature review by expert committee including a range of study designs
Recommendations based on consensus
JNC 8 Critical questions and review criteria defined
by expert panel with input from methodology team
Initial systematic review by methodologists restricted to RCT evidence
Subsequent review of RCT evidence and recommendations by the panel according to a standardized protocol
JNC 7 vs JNC 8: Treatment Goals
JNC 7Separate treatment goals defined for
“uncomplicated” hypertension
Subsets with various comorbid conditions (diabetes and CKD)
JNC 8Similar treatment goals defined for all hypertensive populations
Except when evidence review supports different goals for a particular subpopulation
26
JNC 7 vs JNC 8: Scope of topics
JNC 7
Addressed multiple issues
blood pressure measurement methods
Patient evaluation components
Secondary hypertension
Adherence to regimens
Resistant hypertension
Hypertension in special populations
Based on literature review and expert opinion
JNC 8
Addressed a limited number of questions, those judged by the panel to be of highest priority.
Evidence review of RCTs
JNC 7 vs JNC 8: Review process prior to publication
JNC 7
Reviewed by the National High Blood Pressure Education Program
Coordinating Committee
a coalition of 39 major professional
Public and voluntary organizations and 7 federal agencies
JNC 8
Reviewed by experts including those affiliated with
Professional
Public organizations
Federal agencies
No official sponsorship by any organization should be inferred
ASSESSMENT OF EFFICACY CRITERIA
4.1 BLOOD PRESSURE:
Goal of treating hypertension?
Surrogate endpoint?
When an IND will be acceptable?
4.2 MORBIDITY AND
MORTALITY:
Positive effects on
morbidity and mortality
evaluated properly in
large-scale and long-term
controlled clinical trials
What if results are not
available?
4.3 TARGET ORGAN DAMAGE :
Target organ damage is
presumably and plausibly
associated with morbidity; holds
true for…
Relevant information on the
comparative effectiveness of a new
agent will be obtained
What still remains to be
established?
5. METHODS TO ASSESS EFFICACY
5.1 BLOOD PRESSURE
blood pressure lowering effects documentation- pre-/post-treatment reduction of BP
Preferred efficacy variable and mandatory secondary endpoint?
Response criteria of IND(antihypertensive agents)?
Peak trough ratio?(main focus on trough BP i.e residual effect)
Imp points:
Standardized conditions(posture, time,temp)
WAYS OF MEASURING BP
Sphygmomanometry
Intra-arterial measurements
Non-invasive ambulatory blood pressure
monitoring
Automatic self (home) measurement
ad a) sphygmomanometry
Use of calibrated sphygmomanometer, if not
Aneroid manometer not recommended?
Imp points:
Cuff size, SBP & DBP recording, average of readings
In both arms
Exclusion of patient from study(difference more than 20 for SBP and more than 10 for DBP)
Posture and maintaining posture (additional standing and during exercise)
No shifts and standardized conditions
DESCRIPTIONArterial line48 inches of non-compressible rigid-walled, fluid filled tubingPressure transducer and automatic flushing systemPressure bag and automated slow infusion (1-3mL/h) of pressurised salineElectronic transducer amplifier display
IINTRA-ARTERIAL MEASUREMENT
ad b) Intra-arterial measurements
When used?
Main purpose- relation between dose, magnitude ,duration of effect, changes during exercise, measuring 24 hr efficacy.
Disadv of method
Due to disadv this method can be regarded as a valuable method in initial therapeutic studies but not applicable in clinical pivotal studies
Ad c)non-invasive ambulatory blood pressure monitoring(ABPM)
Strongly recommended although insufficient data to accept ABPM
Recorders used must be validated e.g- AAM-IBHS
Repetitive investigations should be performed on a comparable day using same instrument throughout the study.
Sufficient frequency of readings
Time intervals short & justification should be given in protocol)
Per 24hrs readings have to be evaluable
Day time 2 reading & night time one reading hourly
Other recommendation-
Shd cover time before drug intake as well as1 & 2 hours after wake up
At least 8 measurements between 18 and 24 hrs after drug intake
ANALYSIS:Mean values for day and night
time periods separately
Special analysis to assess trough-
to-peak ratio
Early morning rise
Drop in night time pressure
ad d) automatic self (home) measurement
Automatic devices
In case of treatment cessation
Adv and disadv (can’t be considered as the sole basis for the evaluation of efficacy)
Validation is essential
Insufficient data available to accept
TARGET ORGAN DAMAGE
Need to assess LVH and degree of LVH
To assess LV diastolic function & arterial compliance
Assessment of changes in renal function
Assessment of renal blood flow &/or glomerular filtration rate
Assessment of retinal arteries, retina and papilla
Assessment of arteriosclerotic plaques/increased vascular mass/increased intimal-medial thickness
Special emphasis on the effects in elderly patients and patients with co morbidity
Special attention to patient above 75 yrs of age
CVS morbidity evaluation
Adjudication regarding causes of death and morbidity will be necessary.
MORBIDITY & MORTALITY
6.SELECTION OF PATIENTS
6.1 Study Population
Depends on the etiology and the type of hypertension for which the drug is intended
Population for evaluation of efficacy and safety of a new anti-HT drug
Gender in balanced way
Patients with more severe stages of hypertension need to be included & add on design is appropriate.
Ethnic peculiarities and concomitant illnesses
Need for data in elderly patients(≥ 75yrs) for both efficacy and safety.(PK, DR curve, safety data)
CONT
Salt intake & other non-pharmacological measures should be kept constant
Patients with secondary hypertension and isolated systolic hypertension should be studied separately if indication is specifically claimed
Treatment of hypertension in pregnancy which should also take into account the obstetrical and paediatric aspects of the problem ( give details of pregnancy hypertension clinical trial)
STRATEGY DESIGN
Run in period and washout for patients who were on anti-HT therapy
Time for washout?- Of at least 2 to 4 weeks varies but ranges from weeks to months
Allocation of study drug only if basic blood pressure is stable
Now evaluation of- PD,PK, DI, efficacy/therapeutic studies
7.1 PD
Evaluations of tolerability
Duration of action
Hemodynamic parameters
Neurohumoral parameters
Mechanism of action
Which tests will be performed depend on the drug and its characteristics and chosen tests should be justified by the applicant.
Special studies in elderly depending on route of elimination, in patients with varying degrees of renal dysfunction and/or hepatic dysfunction.
7.2 PK
7.3 INTERACTIONS
Interaction information provide helps in treatment algorithms
Special attention potentially useful or unwanted interactions with drugs which might be
used for combined treatment or in co morbid conditions
Special PK /PD interaction studies should be performed if results of clinical trials or the
PK & PD properties of the drug give reason to specific interactions
7.4 THERAPEUTIC STUDIES
Evaluation of efficacy- Dose-response studies
Randomized, placebo-controlled and double blinded
using at least 3 dosages & optimal dose
Justification of pivotal studies dose schedule
Clearly defined schedules for elderly patients
Robust evidence of its efficacy compared to placebo
Demonstrate contribution of each dose chosen
CONT
Evaluation of efficacy-Controlled trials:
Reference therapy includedAiming at demonstrating similar efficacy/safety ratioPlacebo-controlled withdrawal phases can be introduced at the end of the studyMandatory to assess the combination effect of IND with other std ant-HT agentSpecial attention on reduction of the antihypertensive effect by time (tachyphylaxis)Careful consideration on patients who fail to complete the study per protocol
PATIENTS
For efficacy studies- patients should reflect target
Generally include patients with mild to moderate HT, but patients with severe HT should be enrolled as appropriate
Sample size depends on the target variable and its variance
Subgroup analysis in order to demonstrate consistency across groups
Dose response studies as parallel group studies
Comparative studies should be double blind and randomized(following run-in-period of 2/4wks)
Dose escalation should be as per protocol and duration of treatment long enough to estimate the effect of respective dose
Parallel group design using fixed doses instead escalating in some studies
IND as monotherapy or combined underlying therapy
Duration?
DESIGN AND STUDY DURATION
FOR DOSE RESPONSE- at least 3, preferably 6 months(to demonstrate efficacy) and each tested dose should be mentioned over at least 4 weeks(if more than 1 dose used)
CONTROLLED STUDIES WITH REF AGENTS: should last even longer up to 6 months( for comparison w.r.t ADR as well)
8. SAFETY ASPECTS
8.1 HYPOTENSION
8.2 REBOUND HYPERTENSION
8.3 EFFECTS ON CARDIAC RHYTHM
8.4 PRO-ISCHEMIC EFFECTS
8.5 EFFECTS ON TARGET ORGAN DAMAGE
8.6 EFFECTS ON CONCOMITANT DISEASES
8.7 EFFECTS ON CONCOMITANT RISK FACTOR(present at the same time)
8.8 IMMUNOLOGICAL REACTIONS(hypersensitivity reactions of skin & other organs),changes in blood cells, and hepatitis.
8.1 HYPOTENSIONEither symptomatic or asymptomaticSpecial attention to orthostasis and first dose phenomenonSpecially at initiation of therapy or at increase of dosage
8.REBOUND HYPERTENSIONWithdrawal phenomenaShould be studied specifically
8.3 EFFECTS ON CARDIAC RHYTHM
Specifically (tachycardiac) pro-arrhythmic effectsEffects on impulse conductionHeart rate, ECG and Holter monitoring at frequent intervals
8.4Pro-ischemic effects
Coronary steal effects with potential hypotensive effect
When suspected, study specifically
8.5 EFFECTS ON TARGET ORGAN DAMAGE Data on blood chemistry, urine analysis and other general laboratory investigationsEffects of alterations in regional blood flow in kidney,heart and brain can be studiedSpecial emphasis on renal function,electrolyte homeostasis and LVHOpthalmological examination on suspicion of othalmological side-effectsEmphasis on cognitive functions and CNS effects(dizziness,blurred vision,syncope and TIA)
8.6 EFFECTS ON CONCOMITANT DISEASESWhen specific claims are made , studies are required(From safety perspective IND should not have AE or deleterious effects)
8.9 LONG-TERM EFFETS ON MORTALITY & CVS MORBIDITY
Risk of CVS morbidity & mortality :
strongly associated with HT
Many other risk factor
Therefore, sufficient cohort of patients should
be exposed cont for at least one year
even if specific claims regarding benefit are not made
Need of thorough analysis of study results, preclinical
studies
EPIDEMIOLOGICAL RESULTS HAVE RAISED THE ISSUE WHETHER, DESPITE AN EQUAL BP LOWERING
EFFECT, THE INFLUENCE OF ANTIHYPETENSIVE DRUG ON
MORBIDITY & MORTALITY MAY NOT BE ALIKE.
9. FIXED COMBINATIONS:
9.1 GENERAL REMARKS
A combination of 2 or more actives in a fixed ratio
Why and when?
To obtain a marketing authorisation for a fixed combination,- each active component in the scheduled dosage independently contributes towards
CLINICAL DEVELOPMENT OF A FIXED COMBINATION
Situation where a combination has not yet been demonstrated – need to demonstrate the positive risk/benefits of the joint application of monocomponents
FACTORIAL DESIGN -allows the simultaneous comparison of various dosage combinations with their respective components and with placebo
Ascending dosages of fixed combination could be tested in patients with insufficient response
Clinical studies should be designed in accordance with the indication claimed
Wording of indication must state clearly whether fixed combination should be given as-
FACTORIAL DESIGN
CONT
Wording of indication must state clearly whether fixed combination should be given as-
9.2.1 First line therapy-
9.2.1.1 Sub therapeutic doses
9.2.1.2 Therapeutic doses
9.2.2 Second or third line therapy
9.2.3 Substitution therapy
CONT (FOLLOWING ARE REQUIRED AS A MINIMUM IF FIRST LINE THERAPY CLAIMED FOR A FIXED LOW-DOSE COMBINATION)
1) Demonstration that each substance has a documented contribution within the (fixed) combination- necessary to document significant diff in between placebo & FDC and also bet component of FDC
2) Demonstration of at least similar efficacy to lowest approved doses of each monotherapy compound- BP lowering effect is better or at least similar, inclusion of placebo arm establishes external validity
3) Indication for a reduction of (dose-dependent) ADR by the low dose fixed combination as compared to the components in the lowest approved dosages- better safety as compared to each component
PATIENT SELECTIONAppropriate patient selection is a key point
Inclusion criteria recommendations:
Patients considered for a first line FDC have a low chance to be adequately treated with mono-therapy or by a combination in sub-therapeutic doses.
Risk of CVS events among the included patients is sufficiently high to justify that treatment is initiated with more than one drug
Many other factors are also present- initial BP levels, target BP, concomitant diseases, target organ damage & older age
Pivotal body of evidence should comes from studies conducted in naïve patients fulfilling the recommendation outline above
1.Demonstration of the blood-pressure effect of the substance
Requirements varies depending on substances used in the fixed combination. Following situations are possible:
All substances are well known and the joint application of the two components has proven to be efficacious, safe and thus clinically useful
• Relevant studies either as original or literature based
• One therapeutic confirmatory study
• Long term safety demands by bibliographic data
• Large enough sample for safety assessments & a safety extensions may be necessary- open label design &/or comparative studies with other FDC
One or all substances are not well known &/or efficacy & safety of the joint application have not been established
benefit of the combination will need to be explored further before proceeding to the therapeutic confirmatory study.
Factorial study with comparison between the mono-components & the fixed combination
Design of therapeutic confirmatory study
- Should demonstrate safety & more timely BP control as compared to mono-therapy
- Should be parallel arm design
CONT
Key parameter for evaluation of efficacy is “TIME UNTIL ACHIEVING TARGET BP” . Endpoint is in accordance with the primary aim to achieve the BP goal in a more timely fashion
Special attention on –dose-dependent side effects(1st dose hypotension) & symptoms signs of organ damage (renal dysfunction) , serum electrolyte levels
Caution in patients with DM, autonomic dysfunction & elderly patients
9.2.2 Second-or third-line therapy
Mandatory -at least one or two pivotal clinical study/ies is/are performed
ADD-ON THERAPY-
Not necessarily expected that the dose of the single agent is up-titrated beyond the regular maintenance dose before the second or third agent is added. Selected up-titration dose should be adequately justified
9.2.2 Parallel group comparisons A parallel comparison of the combination with the individual components using the
same therapeutic doses – demonstration of significant superiority & no additional safety concerns
Comparison with another fixed dose combinations may also provide supportive data in the benefit/risk assessment
In some cases (FDC of 2 diuretics) mandatory to show a statistically significant & clinically relevantly superior safety while accepting comparable efficacy
9.2.3 SUBSTITUTION THERAPY
Primary aim- to reduce the number of tablets (enhance the adherence)
The following additional situations are possible:
1. All substances are well known and the joint application of the two or more components is already in widespread use and thus clinically useful-
CONT
Includes cases where the requirements for granting a first line indication or add-on indication are fulfilled
Approach acceptable for where wide therapeutic experience available
Respective data are thoroughly and reliably documented
Comparative PK data are needed( no interactions)
Pivotal data are the BE study showing BE to the components in free combination with the fixed dose.
CONT
2. One or all substances is/are not well known &/or the efficacy & safety of the joint application have not been established
Original clinical data on efficacy & safety for the joint application are required
Benefit/risk of the combination will need to be explored further
Factorial design
An add-on study
Long term safety data
Specific attention to the doses
A) Study designs
A prospective,
Randomized,
Open-label study with blinded assessment of end points
Primary End-points ► Cardiovascular events or death
► Cause –specific first event
► First cardiovascular event
► Coronary event
► Myocardial infarction
► Other cardiovascular event
► Heart failure
► Cerebrovascular event
► Stroke
REFERENCES
1.EMA GUIDELINE ON CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE TREATMENT OF HYPERTENSION
2. ICH E4 DOSE – RESPONSE INFORMATION TO SUPPORT DRUG REGISTRATION
3.ICH E9 – STATISTICAL PRINCIPLES FOR CLINICAL TRIALS
