CTRI/2016/11/007491 [Registered on: 25/11/2016] Trial Registered Prospectively
Last Modified On:
26/11/2019
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Single Arm Study
Public Title of Study
A clinical trial to study the efficacy and safety of combination drugs of chlorthalidone, metoprolol and telmisartan in treatment of high blood pressure with stable coronary artery disease.
Scientific Title of Study
Safety and Efficacy Study of Fixed Dose Combination Tablets of Chlorthalidone, Metoprolol and Telmisartan in the treatment of Essential Hypertension with stable coronary artery disease: An Open label, Multicentric Trial.
P.D.E.As Ayurved Rugnalay & Sterling Multispeciality Hospital Sector No 27,Near Bhel Chowk,Nigdi Pradhikaran,Pune 411 044 Pune MAHARASHTRA
9850337271
dr.karmalkar@gmail.com
Dr Bhushan Kinholkar
Sanjeevan Hospital
Department of Medicine, Sanjeevan Hospital,
OPD No 6, Ground Floor,
Plot No. 23,
Off Karve Road, Erandawane,
Pune- 411004. Maharashtra India.
Pune MAHARASHTRA
02067250000
drbhushankin@gmail.com
Dr Aradhana Sharma
SMS Medical College & Hospital
Department of Medicine, SMS Medical College & Hospital, JLN Marg, Jaipur, India. Jaipur RAJASTHAN
Fixed Dosed Combination tablets of Chlorthalidone (12.5 mg), Metoprolol extended release(25/50 mg) and Telmisartan (40 mg).
Mode of administration: once a day for 24 weeks through oral route.
Comparator Agent
No comparator
No details
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
Inclusion Criteria:
Subjects must meet all of the following criteria to be considered for
enrollment in the study:
1. Male or female patient aged between 18 and 65 years.
2. Patient of stable coronary artery disease (no change in severity of symptoms or nitrate consumption in previous 3 months)
3. Subject with uncontrolled essential hypertension [having seated diastolic BP (SeDBP) 90 to 110 mmHg and seated systolic BP (SeSBP) 140 to 200 mmHg] who is on the stable dose of fixed drug combination therapy of Metoprolol extended release (25/50 mg) + Telmisartan 40 mg for at least 4 weeks.
4. As judged by the Investigator, based on a medical evaluation performed during the screening period. The medical evaluation must include normal or non-clinically significant physical examination, laboratory examination and 12-lead ECG.
5. Patient willing to give informed consent.
6. Female subjects of childbearing potential must be willing to use acceptable method of contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilized, or has not had a hysterectomy at least three months prior to the start of this study. Acceptable method of contraception includes (e.g., barrier method with spermicide). The "calendar method," withdrawal, or an IUD is NOT an acceptable method.
ExclusionCriteria
Details
Exclusion Criteria:
Subjects meeting any of the following criteria must be excluded from
enrollment in the study:
1. Presence of any clinically relevant disease/disorder (e.g. severe hepatic impairment, chronic renal failure, thromboembolic disorders, coronary artery or cerebrovascular diseases, uncontrolled diabetes, uncontrolled thyroid disorder etc.)
2. Surgical or medical condition that, in the judgment of the Investigator or Sponsor, could interfere with absorption, distribution, metabolism, or excretion of the drugs to be used.
3. Presence or history of secondary or malignant hypertension.
4. Any known cardiac disease/disorder in which any of the study medication is contra-indicated (e.g. severe bradycardia, heart block greater than first degree or significant first degree block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome without pacemaker etc.)
5. Current or recent substance abuse, including alcohol.
6. Refusal or inability to comply with the requirements of the protocol for any reason, including scheduled clinic visits and laboratory tests.
7. Participation in any experimental drug study within 60 days before
screening.
8. Breast feeding or pregnant females or Females with child-bearing
potential who do not follow adequate contraceptive measures.
9. Concomitant or prior (within 60 days of screening) use of any of the following medications: calcium channel blocker, clonidine, aliskerin.
10. Subjects having intolerance, hypersensitivity or any other contraindication to any of the Investigational products.
11. History of HIV, Hepatitis B and Hepatitis C
12. Subjects judged unfit for this study by investigator.
Method of Generating Random Sequence
Not Applicable
Method of Concealment
Not Applicable
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Primary Endpoint(s)
Primary Outcome measure(s) will be:
• Mean change in Seated Diastolic Blood Pressure (SeDBP) between baseline and 24 weeks [Time frame: Baseline, 24 weeks]
• Mean change in Seated Systolic Blood Pressure (SeSBP) between baseline and 24 weeks [Time frame: Baseline, 24 weeks]
Baseline-24 weeks
Secondary Outcome
Outcome
TimePoints
Efficacy evaluation:
•Mean change in Seated Diastolic Blood Pressure from baseline
•Mean change in Seated Systolic Blood Pressure from baseline
•Proportion of patients achieving SeDBP less than 90 mmHg (SeDBP responder)
•Proportion of patients achieving SeSBP less than 140 mmHg (SeSBP responder)
•Evaluation of CGI-S from baseline
•Evaluation of CGI-I
Safety Evaluation:
•Adverse events
Baseline-24 weeks
Target Sample Size
Total Sample Size="242" Sample Size from India="242" Final Enrollment numbers achieved (Total)= "254" Final Enrollment numbers achieved (India)="254"
The present study is a multi-center, open label phase-III clinical trial. Total 242 subjects will be enrolled in the study. Treatment duration will be 24 weeks. At screening visit, after evaluating eligibility criteria subjects will be eligible for enrolment visit.
On enrolment visit, subject will be given Fixed Dosed Combination tablets of Chlorthalidone (12.5 mg), Metoprolol ER (25/50 mg) and Telmisartan (40 mg). After enrolment visit, weekly visit (Visit 3, visit 4, visit 5 and visit 6) will be carried out for one month. Subsequent visits: Visit 7 (week 8/ 56 ± 2 days), Visit 8 (week 12/ 84 ± 2 days), Visit 9 (week 16/ 112 ± 2 days), Visit 10 (week 20/ 140 ± 2 days), Visit 11 (End of study visit; week 24/ 168 ± 2 days). During the above visits, if the blood pressure is not adequately controlled as per investigator then appropriate measure (including but not limited to- providing other medications, life style or diet changes, behavior modifications) must be ensured and such patients will be given rescue medications and excluded from the study.
Evaluation criteria will be: Seated Diastolic Blood Pressure (SeDBP), Seated Systolic Blood Pressure (SeSBP), CGI-S scale, CGI-I scale. Safety assessment will be done by evaluating any adverse/serious adverse events and laboratory parameters during entire study period.
Principal-Findings
Our study showed that
in 254 hypertensive patients (SeDBP > 90 mm of Hg and SeSBP > 140
mm of Hg), when a third
drug (Chlorthalidone 12.5 mg) is added to a fixed drug combination of two drugs
(Metoprolol extended
release (25/50 mg) + Telmisartan 40 mg)
and giving these three drugs as a FDC (Chlorthalidone 12.5mg + Metoprolol extended release (25/50 mg) +
Telmisartan 40 mg)
for 24 weeks led to a significant improvement both statistically and clinically
in both SeDBP and SeSBP parameters. It was not only rapid (as early as by week
4) but was also sustained till 24 weeks in both SeDBP and SeSBP parameters.
Both therapeutic goals, individual
(SeDBP < 90 mm of Hg or SeSBP < 140 mm of Hg) and combined (BP < 140 /
90 mm of Hg) were achieved in majority of the patients by the end of study
(week 24). The patterns of results were similar in both ITT and PP population
Triple combination treatment was safe
and well tolerated.
Demography
Mean age, weight,
height and BMI were 48 to 50 years, 63 to 64 kg, 155 cm and 26 kg/m2
respectively in ITT population. Our findings were similar to the one reported
by Bharatia R et al, 2016. They reported mean age, weight, height and BMI were
51.2 years, 71.6 kg, 162.3 cm and 27.3 kg/m2 respectively. Hence, a
demography characteristic of study population in our study was similar to other
study conducted in India.
In present study, mean SeDBP and mean
SeSBP at baseline were in range of 96 to 98 and 155 to 164 mm of Hg respectively.
In studies conducted by several researchers, baseline SeDBP was reported to be
in the range of 97.9 to 103.6 mm of Hg and baseline SeSBP was reported to be in
the range of 157.3 to 166.8 mm of Hg. [i],[ii],[iii] Thus, systolic and diastolic blood
pressure at baseline was similar to other studies conducted in India.
Efficacy
In
our study reduction in SeDBP from baseline by week 4 was around 11 to 11.5 mm
of Hg whereas for SeSBP it was around 18 to 23 mm of Hg in both arms. We have
further observed that by day 168 (24 weeks) reduction in SeDBP and SeSBP from
baseline was around 13-15 mm of Hg and around 27 to 34 mm of Hg respectively.
Balraj et al. (2015) reported a
reduction of 4 mm Hg in SeDBP and 9 mm Hg in SeSBP as early as by day 30 when a
FDC of Telmisartan 40 mg +Amlodipine 5 mg + Hydrochlorothiazide 12.5 mg was
administered to non-responders (who were uncontrolled on dual drug therapy with
FDC of Telmisartan-Amlodipine or FDC of Telmisartan-Hydrochlorothiazide). At
day 120, reduction from base line in SeDBP and SeSBP was approximately 20 mm of
Hg and 30 mm of Hg respectively. The combined therapeutic goal (BP < 150/90
mm of Hg) was attained in 30 % patients by day 30 and 100 % by day 120. We have
also observed that combined therapeutic goal (BP < 140/90 mm of Hg) was attained
in 29 to 51% patients by day 28 and 58 to 71 % by day 168.
Safety
data
In our study no serious events were reported
during the study period. 25 events were reported in 24 patients during the
study period. Out of 25 events reported, 16 events were reported in FDC of
Chlorthalidone (12.5 mg), Metoprolol succinate extended release (25 mg) and
Telmisartan (40 mg) group [Test 1] and 9 events were reported in FDC of
Chlorthalidone (12.5 mg), Metoprolol succinate extended release (50 mg) and
Telmisartan (40 mg) group [Test 2]. Out of 25 events reported, 6 events were possibly
related to study drug [3 events were mild in nature and 3 events were moderate
in nature]. The distribution of six related events were same (three in each
arms) in both test arms. Out of 25 event, 19 events were not related to study
drug [11 events were mild in nature and 8 events were moderate in nature]. All
the adverse events reported were resolved during the study period. There was
only one patient (03902) who was withdrawn from the study due to safety
reasons.
In our study headache was the most common adverse event
reported in both arms. Other events were: Blood glucose increased, Asthenia, Pain,
Nasopharyngitis, Pharyngitis, Blood
creatinine increased, Myalgia, Dizziness, Cough in both arms. Incidences of
these events ranges from 0.7% to 2.2%. One patient with asthenia was
discontinued from the study.
Both arms were comparable with respect
to other safety parameters also. The physical examination, ECG, vital signs and
laboratory findings were within acceptable or non-significant range in both the
arms. The Laboratory AEs did not vary significantly between all the arms. Apart
from the safety that is already known for the study medications, no new safety
findings were observed in the study. The results of safety analysis showed that
the incidence of TEAEs and ADRs were comparable and acceptable in all the arms
with no significant differences were found in other safety parameters like
vital signs, ECG, physical examination and laboratory parameters. Based on
above findings all the arms did not raise any new & significant safety concerns
and showed acceptable safety profile in diabetic patients after receiving the
treatment for 24 weeks.
Conclusion
and further implications
In
summary, Based on the study results, it is concluded that FDC of three drugs
(Chlorthalidone 12.5 mg + Metoprolol extended release (25/ 50 mg) + Telmisartan
40 mg) is safe and effective in patients who do not respond adequately to FDC
of two drugs (Metoprolol extended release (25 mg) + Telmisartan 40 mg) or (Metoprolol
extended release (50 mg) + Telmisartan 40 mg). Since, uncontrolled hypertension
is a major health concern in India, the availability of these drugs
(Chlorthalidone 12.5 mg + Metoprolol extended release (25/ 50 mg) + Telmisartan
40 mg) as a rationale fixed dose combination in a single tablet will help in
controlling BP in patients not adequately responding to dual combination
therapy and achieving therapeutic goal in addition to offering additional
advantage in terms of compliance and adherence to the therapy.
[i] Bharatia R, Chitale
M, Saxena GN, Kumar RG, Chikkalingaiah,Trailokya A, Dalvi K,Talele S Management
Practices in Indian Patients with Uncontrolled Hypertension. J Assoc Physicians India. 2016; Jul 64
(7): 14-21.
[ii] Balraj MS, Arif A,
Faruqui AA: Efficacy and safety of triple drug fixed-dose combination of
Telmisartan, Amlodipine and Hydrochlorothiazide in the management of hypertension.
Int J Res Med Sci. 2015; 3 (8):
1858-1862.
[iii] Maladkar M, Verma V,
Narsikar K, Walinjkar R, Patil W, Saggu N and Kulkarni S.(2012): Triple drug
combination of Telmisartan, Amlodipine and Hydrochlorothiazide in the treatment
of essential hypertension. Open Journal
of Internal Medicine, 2, 67-7.