CTRI/2019/11/022045 [Registered on: 18/11/2019] Trial Registered Prospectively
Last Modified On:
10/12/2020
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group Trial
Public Title of Study
A Study to Evaluate the Safety and Pharmacokinetics of Methylcobalamin
Nasal Spray
Scientific Title of Study
A Phase III Study to Evaluate the Safety and Pharmacokinetics of Methylcobalamin
Nasal Spray, 500μg (Torrent Pharmaceuticals) and Compare the Efficacy of
Methylcobalamin Nasal Spray, 500μg (Torrent Pharmaceuticals) with NasoB12, 500μg
(Troikaa Pharmaceuticals)
CT/MECO/VB12/19/03_01 version 1.2 dated 12/11/2019
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Sanjay Sharma
Designation
General Manager
Affiliation
Torrent Pharmaceuticals Limited
Address
Torrent Pharmaceuticals Limited
Research Centre,
Village: Bhat-382 428
Dist: Gandhinagar
Gujarat, India Torrent Pharmaceuticals Limited
Research Centre,
Village: Bhat-382 428
Dist: Gandhinagar
Gujarat, India Gandhinagar GUJARAT 382428 India
Phone
079-23969100
Fax
079-23969135
Email
sanjaysharma@torrentpharma.com
Details of Contact Person Scientific Query
Name
Dr Sanjay Sharma
Designation
General Manager
Affiliation
Torrent Pharmaceuticals Limited
Address
Torrent Pharmaceuticals Limited
Research Centre,
Village: Bhat-382 428
Dist: Gandhinagar
Gujarat, India Torrent Pharmaceuticals Limited
Research Centre,
Village: Bhat-382 428
Dist: Gandhinagar
Gujarat, India Gandhinagar GUJARAT 382428 India
Phone
079-23969100
Fax
079-23969135
Email
sanjaysharma@torrentpharma.com
Details of Contact Person Public Query
Name
Dr Sanjay Sharma
Designation
General Manager
Affiliation
Torrent Pharmaceuticals Limited
Address
Torrent Pharmaceuticals Limited
Research Centre,
Village: Bhat-382 428
Dist: Gandhinagar
Gujarat, India Torrent Pharmaceuticals Limited
Research Centre,
Village: Bhat-382 428
Dist: Gandhinagar
Gujarat, India Gandhinagar GUJARAT 382428 India
Phone
079-23969100
Fax
079-23969135
Email
sanjaysharma@torrentpharma.com
Source of Monetary or Material Support
Torrent Pharamceuticals Ltd
Primary Sponsor
Name
Torrent Pharamceuticals Ltd
Address
TORRENT PHARMACEUTICALS LTD, RESEARCH CENTRE,
VILLAGE: BHAT-382 428 DIST: GANDHINAGAR, GUJARAT, INDIA
Dr. Vasantrao Pawar Medical college Hospital & Research center
Centre For Developmental Therapeutics Translational Research 4th Floor near, MRD section in Medical college Vasantdada Nagar Adgaon Nashik-422003, Maharashtra, India Nashik MAHARASHTRA
Part A: Part A of the study shall be conducted as monocentric, open-label,
multiple-dose, single-arm, clinical study in healthy subjects. The dose and frequency of dosing is based on the preclinical evaluation
of the formulation.Each eligible subject will receive 3 doses (6 sprays, i.e., two sprays per dose, one spray in each nostril) of methylcobalamin nasal spray on Day 0, 2 and 7.
Part B:Part B of the study shall be conducted as multicentric, open label,
multiple-dose, two-arm, parallel-group study in patients with serum
vitamin B12 levels 200 pg/mL.Eligible patient in test arm will receive 3 doses
(6 sprays) of methylcobalamin (Torrent Pharmaceuticals) nasal spray (two sprays per dose, one spray in each nostril) on Day 0, 2 and 7 during the treatment phase. Thereafter, each patient in test treatment arm will receive 2 doses (4 sprays) of methylcobalamin nasal spray (two sprays per dose, one spray in each nostril) once
each on Day 14 and 21 during the maintenance phase.
Part B:Part B of the study shall be conducted as multicentric, open label,
multiple-dose, two-arm, parallel-group study in patients with serum
vitamin B12 levels 200 pg/mL. In comparator arm, each eligible patient will receive 7 doses (14 sprays) of Naso-B12 (Troikaa Pharmaceuticals) nasal spray
(according to the prescribing information) (two sprays per dose, one spray in each nostril) on alternate days (Day 0, 2, 4, 6, 8, 10, 12)
over two weeks time during the treatment phase. Thereafter, each patient in comparator arm will receive 2 doses (4 sprays) of Naso-
B12 nasal spray (two sprays per dose, one spray in each nostril) once each on Day 14 and 21 during the maintenance phase.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
Part A Inclusion Criteria
1. Male or female subjects of 18-45 years of age
2. Subject voluntarily give written informed consent to participate in the study.
Part B Inclusion Criteria
1. Male or female patients of 18-65 years of age
2. Patient with serum vitamin B12 levels <200pg/mL
3. Patient voluntarily give written informed consent to participate in the study
ExclusionCriteria
Details
Part A:Exclusion Criteria
1. Subject with a history of hypersensitivity to intranasal administration of vitamin B12 or its excipients or any intranasal preparations.
2. Subject who have taken any medication by intranasal route or have used any vitamin supplement within the past 72 hours prior to screening.
3. History of consumption of vitamin supplements i.e. as prescribed medication in the last 14 Days or over-the-counter medication/ herbal remedies in the last 7 Days prior to screening. Subjects currently on treatment with drugs, which
interfere with folate or folic acid metabolism and serum vitamin B12 assay (e.g., cholestyramine, methotrexate, pyrimethamine,
proton pump inhibitors, trimethoprim, etc.)
4. Subject with clinically significant abnormal nasal or respiratory tract conditions, for example, atrophic rhinitis, nasal polyp,
upper respiratory tract infection etc. which may alter the absorption of the study investigational product.
5. Subject having any clinically significant medical illness that would compromise safety of the subject or study outcome/serum vitamin B12 levels as per investigator opinion
6. Subjects with liver enzymes (Alanine
transaminase, Aspartate transaminase, Alkaline phosphatase) > 2.5X the upper limit of normal value (ULN) or total bilirubin >1.5X of ULN or serum creatinine >1.5X of ULN at screening and considered clinically significant by the investigator.
7. History of alcohol or drug abuse or tobacco sniffing.
8. Subjects with known cases of haemoglobinopathies (e.g history of thalessemia minor/major, sickle cell anemia etc.).
9. Subject with clinically abnormal findings on physical examination, vital signs, electrocardiogram and laboratoryinvestigations at screening
10. Subjects positive for Hepatitis B surface antigen (HBsAg),Hepatitis C antibody and human immunodeficiency virus (HIV)antibody test.
11. Subject with positive breath-alcohol test at enrolment.
12. Subject with positive opiate, tetrahydrocannabinol (THC),amphetamine, barbiturates, benzodiazepines or cocaine on
urine test at enrolment or known active alcohol abuse within past 6 months
13. Pregnant or lactating women.
14. In the opinion of the investigator, subject is either unable to cooperate or unlikely to adhere with any study procedure
15. Subjects who have participated in any other investigational drug trial within the past 3 months prior to screening.
Part B:Exclusion Criteria
1. Patients with a history of hypersensitivity to intranasal administration of vitamin B12 or its excipients or any intranasal preparations.
2. Patients who have taken any medication by intranasal route or have used any vitamin supplement within the past 72 hours prior to screening.
3. History of consumption of vitamin supplements i.e. as prescribed medication in the last 14 Days or over-the-counter medication/ herbal remedies in the last 7 Days prior to screening. Patients currently on treatment with drugs, which
interfere with folate or folic acid metabolism and serum vitamin B12 assay (e.g., cholestyramine, methotrexate, pyrimethamine,
proton pump inhibitors, trimethoprim, etc.)
4. Patients with clinically significant abnormal nasal or respiratory tract conditions, for example, atrophic rhinitis, nasal polyp,upper respiratory tract infection etc. which may alter the absorption of the study investigational product.
5. Patients having any clinically significant medical illness that would compromise safety of the patient or study outcome/serum vitamin B12 levels as per investigator opinion
6. Patients with liver enzymes (Alanine transaminase, Aspartate transaminase, Alkaline phosphatase) > 2.5X the upper limit of
normal value (ULN) or total bilirubin >1.5X of ULN or serum creatinine >1.5X of ULN at screening and considered clinically significant by the investigator.
7. Patients with known cases of haemoglobinopathies (e.g history of thalessemia minor/major, sickle cell anemia etc.).
8. Patient with clinically abnormal findings on physical examination, vital signs, electrocardiogram and laboratory investigations at screening
9. Patients who are known seropositive cases of HIV, Hepatitis B or Hepatitis C.
10. Patients with history of recurrent or current abuse of alcohol and drugs of abuse.
11. Pregnant or lactating women.
12. In the opinion of the investigator, patient is either unable to cooperate or unlikely to adhere with any study procedure
13. Patients who have participated in any other investigational drug trial within the past 3 months prior to screening.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
An Open list of random numbers
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Part A:
1) To evaluate the safety and tolerability of methylcobalamin nasal spray in healthy subjects
2)To study serum concentration v/s time of methylcobalamin nasal spray to guide dosing in Part B
Part B:
1) Proportion of patients achieving, serum vitamin B12 levels 200 pg/mL at Day 14
Proportion of patients achieving, serum vitamin B12 levels more than 200 pg/mL at Day 14
Secondary Outcome
Outcome
TimePoints
Part B:Proportion of patients maintaining serum vitamin B12 level 200 pg/mL at the end of 2 weeks of being on maintenance dose (Day 28) in each treatment group
Day 28
Methylmalonic acid (MMA) levels as compared to baseline at
Day 7 and 14 in each treatment group
Day 7 and 14
Reticulocyte count and Reticulocyte Production Index (RPI) as
compared to baseline at Day 7 and 14 in each treatment group
Day 7 and 14
Proportion of patients achieving serum vitamin B12 level 200
pg/mL at Day 7 in each treatment group
Day 7
Proportion of patients achieving serum vitamin B12 level 200
pg/mL at Day 21 in each treatment group
Day 21
Nasal sensory evaluation questionnaire score at Day 14
Day 14
Total amount of vitamin B12 excreted in urine over 12 hours’
time after first dose
12 hours’
time after first dose
Target Sample Size
Total Sample Size="249" Sample Size from India="249" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
Efficacy of methylcobalamin administered via oral or parenteral route has been established in various neurological and haematological disorders associated with vitamin B12 deficiency.
Recently, methylcobalamin has been approved for administration via nasal route as well. Torrent Pharmaceuticals has developed a new formulation of methylcobalamin for administration as a nasal spray.
Based on preclinical exposure and safety data, Torrent Pharmaceuticals proposes to carry out a phase III study to evaluate the safety, tolerability, pharmacokinetic profile and efficacy of its
new formulation methylcobalamin nasal spray. As the efficacy of methylcobalamin is already proven, phase II studies are not required. This study is proposed to be conducted in two parts. After
ascertaining the safety and determining the systemic exposure in first part (Part A), Torrent Pharmaceuticals proposes to evaluate the efficacy and safety of methylcobalamin nasal spray in the second part
(Part B) of the Phase III study. Part A study will be done in healthy subjects, and in Part B study, patients who have subclinical vitamin B12 deficiency will be selected. Part B will commence after
ascertaining the safety of the new formulation and determining the human dose.