H. No.- 8-2-293/82/L/4A,5A and 6A, MLA Colony, Road No. 12, Banjara Hills, 500 034 Hyderabad TELANGANA
9866191476
b_rupam@hotmail.com
Dr Birinder Paul
Dayanand Medical College & Hospital, Research & Development Centre,
Civil Lines, Tagore Nagar, Ludhiana, 141001, Punjab, India
Ludhiana PUNJAB
9878045330
drbirinder06@yahoo.co.in
Dr Sujit Jagtap
Deenanath Mangeshkar Hospital & Research Center (DMHRC)
Erandwane Pune 411004 Pune MAHARASHTRA
919822290200
sujitjagtap@gmail.com
Dr Madhuri Behari
Fortis Flt. Lt .Rajan Dhall Hospital
Room # 25, Department of Neurology, Fortis Flt. Lt. Rajan Dhall Hospital, Sector B, Pocket 1, Arun Asaf Ali Marg, Vasant Kunj, New Delhi- 110070 New Delhi DELHI
911126594856
madhuri.behari@fortishealthcare.com
Dr Hrishikesh Kumar
Institute of Neurosciences Kolkata
Institute of Neurosciences Kolkata, 185/1 A Ajc Bose Road, Kolkata-700017 Kolkata WEST BENGAL
919874645445
rishi_medicine@yahoo.com
Dr Pettarusp Wadia
Jaslok Hospital and Research centre
15, Dr. G. Deshmukh Marg
Pedder Road, Tardeo, Mumbai-400026
Maharashtra Mumbai MAHARASHTRA
9769026664
pettarusp.wadia@gmail.com
Dr Kunal Jadhav
Lifepoint Multispecialty Hospital
145/1, Mumbai Bangalore Highway, Near Hotel Sayaji, Wakad, Pune -411057, Maharashtra Pune MAHARASHTRA
9952684788
kj6398735@gmail.com
Dr Amitkumar Pande
Medipoint Hospitals Pvt.Ltd.
241/1, New D.P. Road, Aundh, Pune- 411007, Maharashtra Pune MAHARASHTRA
9860918000
amitpande411@gmail.com
Dr Jabeen Shaikh
Nizam’s Institute of Medical Sciences
Room # 7, Ground Floor, Department of Neurology, Millennium Block, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad-500082, Telangana
Hyderabad TELANGANA
9704822022
drjabeennims@gmail.com
Dr Charulata Savant Sankhla
P. D. Hinduja National Hospital & Medical Research Centre
Room # 2107, Department of Neurology, P.D. Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim- 400016, Maharashtra
Mumbai MAHARASHTRA
9833977434
charusankhla@gmail.com
Dr Anshu Rohatgi
Sir Ganga Ram Hospital
Room # F20, First Floor, Department o Neurology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi- 110060
New Delhi DELHI
1. The subject has given written informed consent and is willing to participate in the study; 2. Subject is able to understand and comply with all study procedures (requires literacy in available language of all patient-reported outcome measures);
3. Males or females aged ≥ 50 years;
4. Body mass index (BMI) greater than 18.5 kg/m2 and less than 45 kg/m2;
5. Diagnosed with “Clinically Probable PD†according to the MDS clinical diagnostic criteria, with documented diagnosis of PD per treating physician’s records within three years of the Screening visit. Disease severity according to modified Hoehn & Yahr stage ≤ 2;
6. Projected to not require to start dopaminergic therapy within 9 months from Baseline;
7. Female subjects must be not of childbearing potential, e.g., documented evidence that they are surgically sterile (e.g., hysterectomy, partial hysterectomy, bilateral oophorectomy, bilateral tubal ligation), or post-menopausal (at least 12 months since last menses) prior to Screening.
8. Male subjects enrolled in the study should not father a child and are advised to prevent passage of semen to their sexual partner during intercourse using an effective method as judged by the Investigator for the duration of the study and for 3 months after the last dose of study drug;
9. Willingness to undergo lumbar puncture and skin biopsy for future testing of substances related to PD or K0706 target engagement. (For subjects at sites participating in the Biomarker substudy). PART 2:
Subject has completed the part 1 of the study.
2. Subject projected not to need dopaminergic treatment except for treatment with Monoamine Oxidase B (MAOB) inhibitors. MAOB inhibitors will be allowed if the patient was already taking the same during part 1 of the study.
3. Subject has received K0706/placebo, as appropriate, within 4 weeks prior to end of part 1 of the study.
4. Male subjects enrolled in the study should not father a child and are advised to prevent passage of semen to their sexual partner during intercourse using an effective method, as judged by the Investigator, for the duration of the study and for 3 months after the last dose of study drug.
ExclusionCriteria
Details
1. Current, or within 60 days of Screening, use of any prescription, investigational, or over the counter medication for the symptomatic treatment of PD or to slow the progression of PD. Treatment with Monoamine Oxidase B (MAOB) inhibitors will be allowed if the dose is stable for at least 30 days prior to Screening and subjects agree to remain on it for the duration of the study;
2. Prior use of dopaminergic therapy (e.g., levodopa, dopamine agonist, amantadine) for 30 or more days any time in the past;
3. A diagnosis of a significant central or peripheral nervous system disease affecting the subject’s cognition or motor function at any time, such as another neurodegenerative disorder, multiple sclerosis or stroke. This does not include transient neurological deficits such as transient ischemic attacks or migraine aura;
4. A diagnosis of a medical condition that could interfere with interpretation of the MDS-UPDRS during the trial (e.g., musculoskeletal disorders);
5. Contraindications to receiving an MRI;
6. Contraindications to receiving a DaT SPECT (e.g., hypersensitivity to the active substance, any of the excipients, or iodine) if a new DaT SPECT is required for the study;
7. Most recent DaT SPECT scan not compatible with PD (i.e., Scans Without Evidence of Dopaminergic Deficit [SWEDD]) based on central reading by a study physician;
8. MRI scan of the brain performed after onset of PD suggestive of secondary Parkinsonism (e.g., subdural hematoma, normal pressure hydrocephalus, or infarcts of the basal ganglia);
9. Severe tremors as defined by a score of “severe†on any of the MDS-UPDRS Parts 2 or 3 tremor severity (not constancy) items;
10. Montreal cognitive assessment score < 25;
11. History of any surgery on the brain itself including deep brain stimulation for PD (note this does not include surgeries on the skull that do not affect the brain, e.g., small meningioma removal);
12. History of hypersensitivity (e.g., bronchospasm, anaphylaxis, serious drug rash) to contents of the study drug or other tyrosine kinase inhibitors;
13. Clinically significant or unstable psychiatric or medical condition, vital sign, or laboratory abnormality that in the opinion of the investigator interferes with participation in the study;
14. Any clinically significant cardiac abnormality in the opinion of the investigator. This would include myocardial infarction in the six months prior to screening, or significant ECG abnormality, including heart-rate corrected interval QT (QTc) based on Fridericia’s correction formula > 450 milliseconds for males and > 470 milliseconds for females;
15. History or presence of any gastrointestinal disorder or malabsorption syndrome, which might affect absorption of study drug;
16. Subject report of recent (within the previous 6-month) illicit drug use (other than marijuana), or intake of alcohol that is excessive in the opinion of the investigator, or positive urine drug screen at Screening;
17. Subjects report of use of marijuana within one month of Screening or subject not willing to forgo the use of marijuana through the trial;
18. History of surgery within 4 weeks prior to Screening visit or is expected to undergo a planned surgical procedure or invasive diagnostic procedure during the course of the study;
19. Participation in other investigational drug trials within 30 days prior to Screening;
20. Any concomitant medication or medication excluded that could put subject at risk, or interfere with study evaluations (Protocol Section 6.4);
21. Recent use of medications that can cause Parkinsonism and suspicion of the investigator that it could have worsened the subject’s Parkinsonism. This includes neuroleptics (e.g., olanzapine, risperidone, haloperidol), some anti-nausea medications (e.g., prochlorperizine, metoclopramide) and others (e.g., flunarizine, methyldopa);
22. Use of medications that affect the dopaminergic system though do not cause or treat PD, within 60 days of Screening. This includes stimulants (e.g., methylphenidate, amphetamine derivatives, modafinil) and Monoamine Oxidase A (MAOA) inhibitors (e.g., phenelzine, and tranylcypromine). Note that antidepressants are acceptable as long as the subject has remained on them at a stable dose for over 60 days prior to Screening and plans to remain on them through the study;
23. Any malignant disease other than basal cell carcinoma of the skin with evidence of disease within the past 5 years and with the potential for recurrence;
24. Female subjects presently lactating;
Exclusion criteria specific for the Biomarker substudy:
25. Contraindications to undergoing a skin biopsy (e.g., allergy to the anesthetic used, use of anticoagulants or dual anti-platelet agents, history of impaired wound healing, history of keloid formation);
26. Contraindications for performing lumbar puncture such as coagulation disorders, back surgery that might interfere with the procedure, anticoagulants, etc. PART 2Exclusion Criteria: 1. Clinically significant or unstable psychiatric or medical condition, vital sign, or laboratory abnormality that in the opinion of the investigator interferes with participation in the study 2. Any condition that in the opinion of the Investigator represents an obstacle for study conduct and/or represents a potential unacceptable risk for the subject. 3. Subject has any concurrent medical condition or uncontrolled, clinically significant systemic disease (e.g., renal failure, heart failure, hypertension, liver disease, diabetes, or anemia) that, in the opinion of the Investigator, could cause continued treatment to be detrimental to the subject.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Pharmacy-controlled Randomization
Blinding/Masking
Participant, Investigator and Outcome Assessor Blinded
Part 1:
Change from baseline to Week 40 in the sum of the MDS-UPDRS Parts II & III total scores
Part 2:
Change from Week 40 to Week 76 of the long term extension study in the MDS-UPDRS Part III scores
Part 1: Baseline to Week 40 & Part 2: Week 40 to Week 76
Part 1:
Evaluation of slopes of mean MDS-UPDRS part II & III scores over time during part 1 by treatment group
Part 2 :
Evaluation of slopes of the mean MDS-UPDRS parts II & III scores over time in part 2 for of the early-start group as compared to the delayed-start group
Part 1 : Baseline to Week 40 & Part 2: Week 40 to Week 80
Part 1
Change in MDS-UPDRS grand total score (sum of Parts I, II, & III) from the baseline
Part 2 :
Change in MDS-UPDRS grand total score (sum of Parts I, II, & III) from Week 40 (Baseline for part 2) through Week 76
Part 2 :Week 40 to Week 76
Part 2:
Change from Week 40 (Baseline for part 2) through week 76 in MDS-UPDRS Part IA, Part IB, Part I total, Part II total & Part III subscores.
Part 2 : Week 40 through Week 76
Time from the first dose in Part 1 to initiation of symptomatic PD medication.
Part 1: Baseline to Week 40
Proportion of patients starting symptomatic treatment.
Part 1: Baseline to Week 40
Time from Baseline to initiation of symptomatic medication
Part 1: Baseline to Week 40
Change in HRQoL using the EQ-5D-5L from Baseline to Week 40
Part 1: Baseline to Week 40
Change in CGIS from Baseline to Week 40
Part 1: Baseline to Week 40
The Proportion of patients starting symptomatic PD treatment.
Part 2 : Week 40 to Week 80
Change in the mean total MDS-UPDRS Parts I, II & III scores between the early-start & delayed-start groups at 76 weeks
Part 2 : Week 40 to Week 76
Time from Week 40 (Baseline for Part 2) to initiation of symptomatic PD medication in the long term extension study
Part 2: Week 40 to Week 80
Other Outcomes Measures - Part 1
CSF K0706 levels progression or target engagement of K0706
Part 1: Baseline to Week 40 (OPTIONAL)
Change in the SCOPA-AUT from Baseline to Week 40
Part 1: Baseline to Week 40
Pharmacokinetics – Plasma & CSF levels of K0706 & any relevant metabolites
Total Sample Size="506" Sample Size from India="89" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
This study consists of 2 parts. Part 1 of the
study is conducted to evaluate the efficacy, safety, and tolerability of two
doses of K0706 compared to placebo in subjects with early Parkinson’s Disease
who are not receiving dopaminergic therapy. Part 2 is an optional long term
extension study for subjects who have completed week 40 of Part 1. Patients can
choose to participate in Part 2 of the study. The extension study was designed
to evaluate the safety and efficacy of the study drug at 76 weeks.