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1 Clinical Trial Details (PDF Generation Date :- Wed, 31 Oct :40:54 GMT) CTRI Number Last Modified On 30/01/2012 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2012/01/ [Registered on: 30/01/2012] - Trial Registered Prospectively No Interventional Drug Other A clinical study to evaluate the safety, tolerability and pharmacokinetics of novel ZYPH0907, following oral administration in Healthy adult male and female volunteers A randomized, double-blind, placebo-controlled Phase I clinical study to evaluate the safety, tolerability and pharmacokinetics of ZYPH0907, a novel PTH-1r agonist, following oral administration in volunteers Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) ZYPH0907/1001 Ver. 02, 22nd Novmber 2011 Designation Affiliation Protocol Number Details of Principal Investigator Dr Alpeshkumar Patel Principle Investigator Phone Fax Designation Affiliation Sarkhej-Bavla N.H. No. 8A, Moraiya, AhmedabadGujarat, Cadila Healthcare Limited,Zydus Cadila House, TPS 5, Service road,vile Parle(E),Mumbai alpeshkumarjpatel@zyduscadila.com Details Contact Person (Scientific Query) Dr R H Jani Sr VP Phone Fax Designation Affiliation Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad,Gujarat, Cadila Healthcare Limited,Zydus Cadila House, TPS 5, Service road,vile Parle(E),Mumbai rhjani@zyduscadila.com Details Contact Person (Public Query) Dr R H Jani Sr VP page 1 / 7

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Phone Fax > Type of Sponsor NIL List of Countries of Principal Investigator Dr AlpeshKumar Patel Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad,Gujarat, Cadila Healthcare Limited,Zydus Cadila House, TPS 5, Service road,vile Parle(E),Mumbai rhjani@zyduscadila.com Source of Monetary or Material Support Primary Sponsor Details Sarkhej-Bavla N.H. No. 8A, Moraiya,Ahmedabad Gujarat, Pharmaceutical industry-n NIL of Site Site Phone/Fax/ Zydus Research Centre,Clinical Research Department,Cadila Healthcare Limited Survey No. 396/403, Opp. Sarvotam Hotel, Nr. Nova Petrochemicals, Sarkhej-Bavla N.H. No. 8A, Moraiya AlpeshkumarJPatel@zy duscadila.com of Committee Approval Status Date of Approval Is Independent Ethics Committee? Independent Ethics Commitee-Aditya, Ahmdabad Status Approved 05/01/2012 Yes Date Approved/Obtained 09/08/2011 Health Type Healthy Human Volunteers Condition to test the safety of a drug that is expected to be used for osteoporosis Type Details Intervention ZYPH Route of administrration: Oral page 2 / 7

3 2. Dosage:0.025mg, 3. Frequency: Plan I(a single ascending dose study),ii(a single dose food effect study) and III(a single dose in female):zyph0907 shall be administered a single oral dosein the overnight fasting day for 14 days):zyph0907 will be administered once or twice daily for 14 days depending upon the PK results of Plan I(a single ascending dose study). Comparator Agent Placebo 1. Route of administrration: Oral 2. Frequency: Plan I(a single ascending dose study),ii( a single dose food effect study)and III(a single dose in female) Placebo shall be administered a single oral dose in the overnight fasting day for 14 days):placebo will be administered once or twice daily for 14 days depending upon the PK results of Plan I(a single ascending dose study). Intervention ZYPH Route of administrration: Oral 2. Dosage:0.05mg 3. Frequency: Plan I(a single ascending dose study),ii(a single dose food effect study and III(a single dose in female):zyph0907 shall be administered a single oral dosein the overnight fasting day for 14 days):zyph0907 will be administered once or twice daily for 14 days depending upon the PK results of Plan I(a single ascending dose study). Intervention ZYPH Route of administrration: Oral 2. Dosage:0.01mg, 3. Frequency: Plan I(a single ascending dose study),ii(a single dose food effect study) and III(a single dose in female):zyph0907 shall be administered a single oral dosein the overnight fasting page 3 / 7

4 Inclusion Criteria Age From Age To Gender Details Year(s) Year(s) Both Inclusion Criteria day for 14 days):zyph0907 will be administered once or twice daily for 14 days depending upon the PK results of Plan I(a single ascending dose study). 1.Healthy Male or female between 30 and 55 years of age 2.A female subject is eligible to participate if she is of non-childbearing potential 3.Male subjects must agree to use one of the contraception methods 4.BMI within the range kg per m2 5.Capable of giving written informed consent, which includes compliance with protocol 6.QTcB or QTcF less than 450msec. In case of post menopausal women, 1.Postmenopausal women diagnosed as osteoporosis with T score between ranges of -1 to -4 at any one of the two sites measured (lumbar spine and femoral neck). 2.Subjects who are in the opinion of the investigator, likely to comply with the protocol and the investigator s instructions during the study period. 3.Subjects giving informed consent for participation in the study. 4. Subjects who are taking low-dose aspirin for cardiovascular prophylaxis (81mg or less) are eligible to participate in the study, but the aspirin must be discontinued from Screening to the Follow-up visit Exclusion Criteria Details Exclusion Criteria 1.Presence or history of hypersensitivity to any of the active or inactive ingredients of ZYPH0907 formulation 2.History of nephrolithiasis/ urolithiasis in the past 1 year. 3.Abnormal liver function test (ALT/AST more than or equal to 2.5 times UNL) or kidney function test (serum creatinine more than or equal to 2.0 mg/dl and calculated GFR value). 4.Abnormal laboratory values of parathyroid hormone (PTH), Serum Calcium (Ca),and Alkaline phosphatase (ALP). 5.History of hyperuricemia/gout. 6.History of diseases causing malabsorption in the last one year. 7.Subjects with abnormal ECG findings. 8.The subject has a positive pre-study drug/alcohol screen 9.Positive urinary cotinine levels or history or regular use of tobaccoor nicotine-containing products within 6 months prior to screening. 10.History of regular alcohol consumption within 6 months of the study 11.History of sensitivity to heparin or heparin-induced thrombocytopenia 12.Unable or unwilling to abstain from caffeine-or xanthine-containing products for 24 hours prior to dosing until the final post-dose assessment at each treatment level. 13.History or presence of significant drug abuse 14.Use of alcohol for 24 hours prior to dosing until final post-dose assessment at each treatment level. 15.A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening 16.A positive test for HIV antibody page 4 / 7

5 17.Pregnant females as determined by positive urine hcg test at screening or prior to dosing 18.Lactating females 19.Has anemia defined by hemoglobin concentration 11.0g/dL for males or less than 10.0g/dL for females. 20.Abnormal vital signs 21.History of any gastrointestinal or hepatic conditions that could impact absorption of the investigational compound. 22.Family history of torsade de pointes or other ventricular arrhythmias. 23.Family history of unexplained sudden death. 24.Subjects who have asthma or a history of asthma 25.Exposure to more than four new chemical entities within 12 months prior to the first dosing day 26.Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 14 days if the drug is a potential enzyme inducer or 5 half-lives prior to the first dose of study medication, unless in the opinion of the Investigator and CHL Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. 27.Where participation in the study would result in donation of blood or blood products in excess of 500 ml within a 56 day period 28.Unwillingness or inability to follow the procedures outlined in the protocol. 29.As a result of the medical interview, physical examination, or screening investigations, the investigator considers the subject unfit for the study. 30.Subject is either an immediate family member of a participating investigator, study coordinator, employee of an investigator; or is a member of the staff conducting the study. Method of Generating Random Sequence Method of Concealment Blinding/Masking Random Number Table Pre-numbered or coded identical Containers Participant and Investigator Blinded Primary Outcome Outcome Timepoints Safety and tolerability Safety and tolerability Plans I,II and III[upto Day 8] Plan IV [ upto Day 21 ] Secondary Outcome Outcome Timepoints Pharmacodynamics and pharmacokinetics PK: 1.Blood Plans I, II, III: [Time frame: pre dose to 72 hrs post Dose on Day 8] Plan IV: [Pre-dose to 72 hrs post dose on Day 14] 2. Urine: Plans I, II, III: [Time frame: pre dose to 48 hrs post Dose Day 3] Plan IV: [Pre-dose to 48 hrs of first dosing on Day 14] PD: Plan IV [Time frame: Blood and urine sampling on day 1,7 and 14] Target Sample Size Phase of Trial Phase 1 Date of First 15/04/2012 Total Sample Size=96 Sample Size from =96 page 5 / 7

6 Enrollment () Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial () Publication Details Brief Summary No Date Specified Years=0 Months=10 Days=0 Not Applicable Not Yet Recruiting Osteoporosis is a major health problem, particularly for elderly women. It is characterised by diminished bone mass, decreased bone mineral density (BMD), bone strength and associated with an increased risk of bone fracture. Osteoporosis occurs when the rate of the bone resorption is greater than the rate of bone formation. At present, there is no safe and effective orally bioavailable therapy available for the treatment of osteoporosis. Clinically used anti-osteoporosis agents such as Estrogen, Raloxifene, Calcitonin and Bisphosphonate derivatives, only prevent bone resorption and do not contribute towards bone formation. The native human Parathyroid Hormone (PTH) is an 84 amino acids polypeptide. It regulates calcium homeostasis in the human body through its direct action on bone and kidneys. Administration of PTH via parenteral route efficiently increases bone mineral density (BMD), bone strength and reduces the incidence of new osteoporotic fractures in osteoporotic patients. PTH exerts all these effects primarily through its interaction with a cell surface PTH receptor (mainly PTH-1r; a GPCR). PTH binds to the PTH-1r with affinity in the nm range. The primary intracellular effector enzyme activated by the PTH receptor in response to PTH peptide is adenylyl cyclase (AC) and cyclic adenosine monophosphate (camp), which regulates the downstream cellular processes involved in bone remolding. Since PTH regulates blood calcium and the phosphate levels and exhibit potent anabolic (bone-forming) effects, the parathyroid hormone and its derivatives represent potential therapeutic agent for the treatment of osteoporosis. Currently, truncated PTH derivative (34 amino acid PTH peptide), under the brand name Forteo/ teriparatide acetate (Eli Lilly), has been approved for the treatment of osteoporosis. Administration of Forteo via parenteral route efficiently increases bone mineral density (BMD), bone page 6 / 7

7 Powered by TCPDF ( PDF of Trial strength and reduces the incidence of new osteoporotic fractures in osteoporotic patients. Unfortunately, due to the large molecular weight, Forteo cannot be administered via oral route. Also, long term tolerability of Forteo is limit due to increased risk of hypercalcemia and osteosarcoma. Thus, under clinical set-up, interim and cautious use of Forteo is recommended for the treatment of osteoporosis. Therefore, of Cadila Healthcare Ltd developed a novel and orally bioavailable peptidomimetic based PTH-1r agonist (ZYPH0907) for the safe and effective treatment of osteoporosis. page 7 / 7