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.

Phase 3

Completed

• Conditions: Essential (primary) hypertension,

• Registration Number: CTRI/2016/11/007491
• Lead Sponsor: Sun Pharma Laboratories Limited

Brief Summary

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 thatin 254 hypertensive patients (SeDBP > 90 mm of Hg and SeSBP > 140

mm of Hg), when a thirddrug (Chlorthalidone 12.5 mg) is added to a fixed drug combination of two drugs(Metoprolol extendedrelease (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 clinicallyin both SeDBP and SeSBP parameters. It was not only rapid (as early as by week4) 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 safeand well tolerated.

**Demography**

Mean age, weight,height and BMI were 48 to 50 years, 63 to 64 kg, 155 cm and 26 kg/m2respectively in ITT population. Our findings were similar to the one reportedby Bharatia R et al, 2016. They reported mean age, weight, height and BMI were51.2 years, 71.6 kg, 162.3 cm and 27.3 kg/m2 respectively. Hence, ademography characteristic of study population in our study was similar to otherstudy conducted in India.

In present study, mean SeDBP and meanSeSBP 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 bein the range of 97.9 to 103.6 mm of Hg and baseline SeSBP was reported to be inthe range of 157.3 to 166.8 mm of Hg. [[i]](file:///C:/Users/hiren.savla/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/WW51OW2W/CSR-Telmi.docx#_edn1),[[ii]](file:///C:/Users/hiren.savla/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/WW51OW2W/CSR-Telmi.docx#_edn2),[[iii]](file:///C:/Users/hiren.savla/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/WW51OW2W/CSR-Telmi.docx#_edn3) Thus, systolic and diastolic bloodpressure at baseline was similar to other studies conducted in India.

**Efficacy**

Inour study reduction in SeDBP from baseline by week 4 was around 11 to 11.5 mmof Hg whereas for SeSBP it was around 18 to 23 mm of Hg in both arms. We havefurther observed that by day 168 (24 weeks) reduction in SeDBP and SeSBP frombaseline was around 13-15 mm of Hg and around 27 to 34 mm of Hg respectively.

Balraj et al. (2015) reported areduction of 4 mm Hg in SeDBP and 9 mm Hg in SeSBP as early as by day 30 when aFDC of Telmisartan 40 mg +Amlodipine 5 mg + Hydrochlorothiazide 12.5 mg wasadministered to non-responders (who were uncontrolled on dual drug therapy withFDC of Telmisartan-Amlodipine or FDC of Telmisartan-Hydrochlorothiazide). Atday 120, reduction from base line in SeDBP and SeSBP was approximately 20 mm ofHg and 30 mm of Hg respectively. The combined therapeutic goal (BP < 150/90mm of Hg) was attained in 30 % patients by day 30 and 100 % by day 120. We havealso observed that combined therapeutic goal (BP < 140/90 mm of Hg) was attainedin 29 to 51% patients by day 28 and 58 to 71 % by day 168.

**Safetydata**

In our study no serious events were reportedduring the study period. 25 events were reported in 24 patients during thestudy period. Out of 25 events reported, 16 events were reported in FDC ofChlorthalidone (12.5 mg), Metoprolol succinate extended release (25 mg) andTelmisartan (40 mg) group [Test 1] and 9 events were reported in FDC ofChlorthalidone (12.5 mg), Metoprolol succinate extended release (50 mg) andTelmisartan (40 mg) group [Test 2]. Out of 25 events reported, 6 events were possiblyrelated to study drug [3 events were mild in nature and 3 events were moderatein nature]. The distribution of six related events were same (three in eacharms) in both test arms. Out of 25 event, 19 events were not related to studydrug [11 events were mild in nature and 8 events were moderate in nature]. Allthe adverse events reported were resolved during the study period. There wasonly one patient (03902) who was withdrawn from the study due to safetyreasons.



In our study headache was the most common adverse eventreported in both arms. Other events were: Blood glucose increased, Asthenia, Pain,Nasopharyngitis, Pharyngitis, Bloodcreatinine increased, Myalgia, Dizziness, Cough in both arms. Incidences ofthese events ranges from 0.7% to 2.2%. One patient with asthenia wasdiscontinued from the study.Both arms were comparable with respectto other safety parameters also. The physical examination, ECG, vital signs andlaboratory findings were within acceptable or non-significant range in both thearms. The Laboratory AEs did not vary significantly between all the arms. Apartfrom the safety that is already known for the study medications, no new safetyfindings were observed in the study. The results of safety analysis showed thatthe incidence of TEAEs and ADRs were comparable and acceptable in all the armswith no significant differences were found in other safety parameters likevital signs, ECG, physical examination and laboratory parameters. Based onabove findings all the arms did not raise any new & significant safety concernsand showed acceptable safety profile in diabetic patients after receiving thetreatment for 24 weeks.

**Conclusionand further implications**

Insummary, Based on the study results, it is concluded that FDC of three drugs(Chlorthalidone 12.5 mg + Metoprolol extended release (25/ 50 mg) + Telmisartan40 mg) is safe and effective in patients who do not respond adequately to FDCof two drugs (Metoprolol extended release (25 mg) + Telmisartan 40 mg) or (Metoprololextended release (50 mg) + Telmisartan 40 mg). Since, uncontrolled hypertensionis a major health concern in India, the availability of these drugs(Chlorthalidone 12.5 mg + Metoprolol extended release (25/ 50 mg) + Telmisartan40 mg) as a rationale fixed dose combination in a single tablet will help incontrolling BP in patients not adequately responding to dual combinationtherapy and achieving therapeutic goal in addition to offering additionaladvantage in terms of compliance and adherence to the therapy.

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[[i]](file:///C:/Users/hiren.savla/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/WW51OW2W/CSR-Telmi.docx#_ednref1) Bharatia R, ChitaleM, Saxena GN, Kumar RG, Chikkalingaiah,Trailokya A, Dalvi K,Talele S ManagementPractices in Indian Patients with Uncontrolled Hypertension. *J Assoc Physicians India*. 2016; Jul 64(7): 14-21.

[[ii]](file:///C:/Users/hiren.savla/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/WW51OW2W/CSR-Telmi.docx#_ednref2) Balraj MS, Arif A,Faruqui AA: Efficacy and safety of triple drug fixed-dose combination ofTelmisartan, Amlodipine and Hydrochlorothiazide in the management of hypertension.*Int J Res Med Sci*. 2015; 3 (8):1858-1862.

[[iii]](file:///C:/Users/hiren.savla/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/WW51OW2W/CSR-Telmi.docx#_ednref3) Maladkar M, Verma V,Narsikar K, Walinjkar R, Patil W, Saggu N and Kulkarni S.(2012): Triple drugcombination of Telmisartan, Amlodipine and Hydrochlorothiazide in the treatmentof essential hypertension. *Open Journalof Internal Medicine*, 2, 67-7.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-08-08
• Study Completion: 2018-11-15
• Last Update Posted: 2019-11-26

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 242

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.
• Presence or history of secondary or malignant hypertension.
• 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.
• Refusal or inability to comply with the requirements of the protocol for any reason, including scheduled clinic visits and laboratory tests.
• Participation in any experimental drug study within 60 days before screening.
• Breast feeding or pregnant females or Females with child-bearing potential who do not follow adequate contraceptive measures.
• Concomitant or prior (within 60 days of screening) use of any of the following medications: calcium channel blocker, clonidine, aliskerin.
• History of HIV, Hepatitis B and Hepatitis C 12.
• Subjects judged unfit for this study by investigator.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Primary Endpoint(s)	Baseline-24 weeks
Primary Outcome measure(s) will be:	Baseline-24 weeks
•Mean change in Seated Diastolic Blood Pressure (SeDBP) between baseline and 24 weeks [Time frame: Baseline, 24 weeks]	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 Measures

Name	Time	Method
Efficacy evaluation:	•Mean change in Seated Diastolic Blood Pressure from baseline

Trial Locations

Locations (12)

Aster Aadhar Hospital; 🇮🇳 Kolhapur, MAHARASHTRA, India

Gandhi Hospital; 🇮🇳 Hyderabad, ANDHRA PRADESH, India

Government Medical College; 🇮🇳 Aurangabad, MAHARASHTRA, India

Institute of Post Graduate Medical Education and Research; 🇮🇳 Kolkata, WEST BENGAL, India

Kanoria Hospital & Research Centre; 🇮🇳 Gandhinagar, GUJARAT, India

Marudhar Hospital; 🇮🇳 Jaipur, RAJASTHAN, India

N.R.S. Medical college & Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

Osmania General Hospital; 🇮🇳 Hyderabad, ANDHRA PRADESH, India

Oyster & Pearl Hospital; 🇮🇳 Pune, MAHARASHTRA, India

P.D.E.As Ayurved Rugnalay & Sterling Multispeciality Hospital; 🇮🇳 Pune, MAHARASHTRA, India

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Aster Aadhar Hospital

🇮🇳Kolhapur, MAHARASHTRA, India

Dr Avinash Kumbhar

Principal investigator

2316622555

ankumbhar.aacr@gmail.com