Aims and Objectives Primary objective:- To assess whether treatment with oral propranolol, long acting formulation starting from 40 mg up to a dose of 240 mg or maximum tolerated dose improve tremors in patients with SCA 12. Secondary objective:- To assess whether treatment with oral propranolol, long acting formulation starting from 40 mg upto a dose of 240 mg or maximum tolerated dose improve baseline ataxia in patients with SCA 12. To assess whether treatment with oral propranolol hydrochloride starting from 40 mg up to a dose of 240 mg or maximum tolerated dose improve health related quality of life in patients with SCA 12. Rationale for the Study 1. Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant neurodegenerative disorder described in pedigrees of German American and Indian descent associated with an expansion of a CAG repeat in the 5’ region of the gene PPP2R2B which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A. 2. Action tremor is the most common initial presenting symptom as documented in various studies. 100% (Holmes et al, 2003), 67% in CAG= 51, 56% in CAG 43-51 (Srivastava et al,2017) ; 90% (Choudhury et al, 2018) 3. No clinical studies have been done on the efficacy of common anti tremor medications in patients with SCA 12. 4. This study will evaluate the efficacy of commonly used anti tremor medication propranolol in patients with SCA 12 presenting with tremors. 5. The selected dose range is based on most commonly used doses in previous trials. Half life elimination of propranolol- IR- 3-6 hrs, extended release- 8-10 hrs SSC- within 48 hrs) Methodology Study Design: Single centre double blind randomised placebo controlled trial. Study Population: All patients who present to either Ataxia clinic or inpatient/outpatient facilities of the Neurology department of AIIMS, Delhi with a genetically confirmed diagnosis of SCA 12 with tremors. Inclusion Criteria: 1.All genetically proven SCA 12 patients with tremors 2. Age- 18yrs- 65 years 3. Tremor severity score of at least 2 in at least one upper extremity on at least one of the three manoeuvres on the TETRAS scale. Exclusion Criteria: 1.Patients with bronchial asthma, COPD, Peripheral vascular disease, Diabetes Mellitus, Acute Heart failure, heart block, bradycardia with heart rate less than 60 bpm, blood pressure less than 90 mm Hg systolic and 60 mm Hg diastolic. 2.All other possible causes of tremors (hyperthyroidism, parkinsonism, psychogenic tremors, enhanced physiological tremors, drugs like beta agonists ,theophylline, valproate, lamotrigine) 3. Not giving consent 4. Pregnancy and lactation Consent : After eligibility assessment patients and their relatives shall be informed about the procedure. The patients already on propranolol, 2 weeks wash out period will be given before starting intervention. All other anti tremor medications will be continued at the same dose, no increase in dose or addition of new anti tremor drug will be allowed during the study. Analysis Plan: Sample size- Pilot study, minimum sample size of 30 in each arm (total- 60). Randomisation and allocation ✔ Randomization: Block randomization using mixed block size. ✔ Allocation: The groups will be randomly allocated in 1:1 ratio into treatment arm and placebo arm. ✔ Concealment: The allocation will be concealed in a sealed opaque envelope and shall be opened only after patient consent and randomization. ✔ Blinding: Double blinded study. Both the clinician and participant will be blinded Methodology 1. A total of 60 genetically proven SCA 12 patients who fulfil the inclusion criteria will be enrolled into the study. After eligibility assessment, block randomization using mixed group size will be used to randomize the patients into treatment arm and placebo arm in ratio of 1:1. 2. Baseline assessments- Baseline assessment of tremors will be done using TETRAS PS scale as well as TETRAS ADL scale. Baseline assessment of ataxia will be done using SARA scale. Baseline assessment of health related quality of life will be done using SF 36 questionnaire. Quantitative assessment of tremor severity, frequency and characteristics using surface EMG and accelometry. 3. The patients in treatment arm will receive oral propranolol ER starting from a dose of 40 mg. The dose will be uptitrated in increments of 40 mg every week to a maximum of 240 mg or maximum tolerated dose. The titration phase will be for 5 weeks. 4. The patients in placebo arm will receive placebo at appropriate doses maintaining the blinding. 5. The patients will be assessed every weekly, prior to dose escalation during titration phase. 6. If during assessment during titration phase, the patient has achieved a 30% reduction in TETRAS PS or composite TETRAS PS + ADL score from the baseline, the current dosage will not be further increased. 30% reduction is considered as end point on the basis of previous trials of propranolol in ET that demonstrated a mean percent change in tremor of approximately 30% after intervention. 7. If patient develops severe adverse effects (Heart rate < 60 bpm or BP < 90/60), one time dose reduction will be allowed and the dose prior to increment will be continued. 8. After titration phase, the stable drug dose achieved will be continued for further 8 weeks (maintenance phase) and the assessments will be repeated at 4 weeks and 8 weeks of maintenance phase. 9. At the end of 8 weeks of maintenance phase, a repeat surface EMG and accelerometry will be done to quantify the tremor severity, frequency and characteristics. 10. Statistical analysis will be done as per ITT principle using IBM SPSS version 20.0. Results will be expressed as means ± SD and median for continuous variables or as a percentage in categorical variables. Change from baseline will be measured using multivariate ANCOVA with baseline TETRAS PS and total duration of illness as covariates at 2 time points, 4 weeks and 8 weeks post titration. Change from baseline will be expressed as LSM(Least square means) ± SE. For change from baseline in SARA, baseline SARA score and total duration of illness will be considered as covariates. Difference in accelerometric parameters will be assessed by Mann Whitney U test. Plan outline Similar looking tablets of propranolol ER 40 mg and placebo will be used. Doses will be uptitrated as per following schedule- 1 tablet(D1) 2 tablets(D8) 3 tablets(D15) 4 tablets(D22) 5 tablets(D29) 6 tablets(D36) Schedule of visits plus assessments Visit 1- Eligibility assessment- Clinical history, examination, routine blood tests, ECG, Chest X ray, Recording of symptoms and examination at onset from previous records, Visit 2- Randomization Visit 3- Baseline assessment (D0)- Clinical examination, TETRAS PS +ADL, SARA, SF 36, surface EMG + accelometry Visit 4- After 1 week of dose 1 (D7)- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 5- After 1 week of dose 2 (D14)- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 6- After 1 week of dose 3 (D21)- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 7- After 1 week of dose 4 (D28)- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 8- After 1 week of dose 5 (D35)- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 9- After 1 week of dose 6 (D42)- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 10- After 4 weeks of maximum tolerated dose/ dose 6- Clinical examination, TETRAS PS +ADL, SARA, SF 36 Visit 11- After 8 weeks of maximum tolerated dose/ dose 6- Clinical examination, TETRAS PS +ADL, SARA, SF 36, surface EMG + accelometry At each visit, compliance will be checked by pill count. The patient will be asked to maintain a diary of 12 hrly BP and pulse recordings along with any other side effects encountered, which shall be assessed at each visit. Outcome analysis 1. Primary outcome- To assess the change in TETRAS PS scores and composite of TETRAS PS + ADL scores from baseline at 4 weeks and 8 weeks of maintenance phase (On stable drug dose achieved) 2. Secondary outcomes- a. To assess the change in SARA scale from baseline at the end of 4 weeks and 8 weeks of stable drug dose achieved. b. To assess the change in health related quality of life using SF 36 questionnaire from baseline at the end of 4 weeks and 8 weeks of stable dose. c. To assess the change in quantitative assessment of tremors, peak frequency and peak power using surface EMG and accelerometry at the end of 8 weeks of stable dose achieved. Safety assessment At each visit, patients would be assessed for drug compliance (by pill count method) and asked for adverse effects. Standard definitions for adverse events and serious adverse events (SAE) shall be followed. The details of any adverse reactions occurring anytime during treatment will be recorded. For each adverse event, action taken, outcome, intensity and relationship to intervention will be recorded. The SAEs will be notified to the DSMB and IEC within 24 h. Unscheduled visits- Patients will be encouraged to consult via telephone or physically in case of any problems. In case of unscheduled visits/consultations, reasons for the same would be noted along with assessment for compliance, adverse effects. Appropriate investigations would be done in case any symptom/sign of adverse effects and managed clinically. Withdrawal from the study- If a patient experiences severe adverse event due to the study drug that necessitates stopping the treatment, the patient would be withdrawn from the study and managed clinically. Data Safety monitoring board- An independent data safety monitoring committee shall be constituted to monitor the safety of the intervention used. The meeting of DSMB shall take place once half of the proposed sample size has been recruited. Management guidelines for adverse events- • Patient will be telephonically consulted on day 1 and and on the next day of dose increment for any side effects. The dose will be titrated to maximum tolerated dose. If patient develops adverse events after increment, the dose prior to increment will be continued. • Pulse rate, blood pressure monitoring will be encouraged before dose increment and the patient will be asked to maintain a home BP, Pulse chart. • Patient will be physically evaluated in each of the scheduled visits along with unscheduled visits • Appropriate and prompt measures would be taken for any other adverse effects on case to case basis.
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