Study to Investigate the Effect of Hypoestes Rosea Powder in Parkinson's Disease
Study to Investigate the Effect of Hypoestes Rosea Powder in Parkinson's Disease
Parkinson's disease (PD) is a progressive neurological disease characterized by resting
 tremors, limb stiffness, impaired balance, and slow movement. There is no known cure for PD
 although levo-3,4 dihydroxyphenylalanine (L-DOPA) and dopamine agonists are effective for
 improving PD symptoms in the early years following diagnosis. Hypoestes rosea is an evergreen
 shrub which has anti-inflammatory, anticancer and antimalarial properties. Recent studies
 showed that the active pharmaceutical ingredient (API) of Hypoestes rosea, Hypoestoxide, was
 effective in modifying disease progression in a transgenic mouse model of PD.

 The aim of this study is to determine the efficacy of Hypoestoxide, as contained in Hypoestes
 rosea dry leaf powder, in improving motor symptoms in consenting PD patients. The study
 design is a double-blind, placebo-controlled cross-over trial involving 30 patients with mild
 to moderate disease (Stages 1-3 of Hoehn and Yahr scale over an 8-week period. The symptoms
 of the participants will be monitored using mobile phones with an established quantitative
 assessment tool, mPower2.0, which was previously developed for monitoring symptoms and
 disease progression in PD patients. In addition, the motor examination component of the
 International Movement Disorders Society scale will be administered and correlated with the
 finding on the mobile phone. The outcome measure is an improvement in the motor variables of
 the study participants with a 10% change from baseline over the 8 weeks of using Hypoestes.
Justification Age-associated disorders are increasing in many low- and middle-income
 countries due to population ageing and changing lifestyles. PD is a devastating condition
 which, in the advanced stages, is associated with immobility and uncontrollable tremors. Life
 then becomes miserable for the sufferers. Unfortunately, there is no cure for the disease
 except control of symptoms with medications. Any treatment combination that leads to better
 symptom control will go a long way in improving the quality of life for PD patients. This
 proof of concept study, if successful will give a new lease on life to PD patients. Hence it
 is considered worthwhile to treat PD patients with a new compound that is contained in a
 local plant that is readily available and holds promise for efficacy based on its mode of
 action specifically in reducing the formation of alpha synuclein which underlies the neuronal
 death in PD.

 OBJECTIVES OF THE STUDY

 The aim of this study is to determine the efficacy of Hypoestoxide, as contained in Hypoestes
 rosea dry leaf powder, in improving motor symptoms in consenting PD patients over an 8-week
 period.

 Specific Objectives:

 -  To determine the efficacy of Hypoestes rosea in improving motor performance of PD
 patients through traditional clinical evaluation, use of the selected components of the
 Motor Examination section of the International Movement Disorders Society Scale and the
 computer software application (mPower2.0 app)

 -  To document the side effect profile of the herbal product

 Methodology Study site: University College Hospital, Ibadan Study design: Single-center,
 randomized, double-blind, placebo-controlled trial Study Type: Interventional (Clinical
 Trial) Allocation: Randomized Masking: Double Primary Purpose: Treatment Study participants:
 Patients with mild to moderate Parkinson's disease symptoms.

 Eligibility Criteria Ages eligible for study: 30 years and older (Adult, older adult) Sexes
 Eligible for Study: All Accepts healthy volunteers: No Sample size: Being a proof-of-concept
 study, 30 PD patients will participate in this phase of the study

 Inclusion criteria:

 -  Willing and able to give informed consent.

 -  Willingness and ability to comply with study requirements.

 -  PD diagnosis must be confirmed by bradykinesia plus one of the other cardinal signs
 (resting tremor, rigidity, postural instability) being present.

 -  Age >30 years

 -  Men and women with mild to moderate PD: Hoehn and Yahr scale stages 1 - 3. Participants
 may be on current therapeutic agents (including levodopa, dopamine agonists,
 anticholinergics, amantadine or selegiline) to treat PD symptoms at the time of
 enrollment and may remain on these agents throughout the 5-month study period.

 -  Women of childbearing potential (i.e., those not postmenopausal or surgically sterile)
 may participate provided that they are using adequate birth control methods for the
 duration of the study. Women of childbearing potential must have a negative pregnancy
 test at baseline and be non-lactating.

 Exclusion:

 • Subjects with advanced, severe disease, including those with dementia, severe
 osteoarthritis, allergies, stroke, and visual impairment.

 -  Presence of atypical PD syndromes due to drugs (e.g., metoclopramide, flunarizine),
 metabolic identified neurogenetic disorders (e.g., Wilson's disease), encephalitis, or
 other degenerative diseases (e.g., progressive supranuclear palsy).

 -  Any clinically significant medical condition (e.g., active neoplasm, angina) or
 laboratory abnormality, which would in the judgement of the investigator interfere with
 the subjects' ability to participate in the study or be followed.

 Study Procedure:

 In this study, participants with mild to moderate PD, whether treated or untreated, will be
 randomized into one of two study arms following an initial baseline assessment to determine
 motor activity status of each participant as follows:

 Baseline Determination: Measurement of motor activities of all participants will be
 determined for 3 weeks while on regular PD medication(s). The International Movement
 Disorders Society Scale - Motor Examination (10 selected items on Slowness, Posture, Tremor,
 Rigidity and Gait) will be utilized for the quantitation of the motor activities.

 Drug arm: 15 patients will receive 4 capsules each containing 350 mg orally twice a day of
 Peko-D Forte for 8 weeks as add-on therapy to patients' regular PD medication(s).

 Placebo arm: 15 participants will receive 4 capsules orally twice a day of USP-grade starch
 for 8 weeks as add-on to regular PD medication(s).

 Wash-Out: Wash-out will be for a duration of 4 weeks in which patients assigned to both arms
 will take no capsules.

 The Switch over: Following the wash-out period, the Peko-D Forte group will receive 4
 capsules of USP-grade starch powder taken orally twice a day for 8 weeks. The placebo group
 will receive 4 capsules of Peko-D Forte taken orally twice a day for 8 weeks.

 Symptoms of the participants will be monitored using traditional clinical evaluation and
 daily using mobile phones installed with an established quantitative assessment tool,
 mPower2.0, previously developed for monitoring symptoms and disease progression in PD
 patients.26 Once enrolled and given the smartphones and mPower2.0 app, the participants will
 be asked to perform four (4) separate study tasks daily during the baseline determination
 period and throughout the treatment period: gait, tremor, tapping and balance. The
 International Movement Disorders Society Scale (MDS) - Motor Examination (10 selected items
 on Slowness, Posture, Tremor, Rigidity and Gait) will be utilized for the quantitation of the
 motor activities. Data collected using mPower2.0 and the MDS - Motor items will then be
 analyzed for significant changes in symptom severity relative to baseline status.

 OUTCOME MEASURE: 10% Mean change in motor assessment parameters using the International
 Movement Disorders Society Scale - selected motor examination items while on the Hypoestes.
 This equates to 1- to 2-point improvement in motor performance over a 2-month period on
 Hypoestes in the absence of side effects which will be monitored using pharmacovigilance
 tools.

 Total duration of study: 5 months (2 months on active drugs, 2 months on placebo with one
 month wash-out period in-between)

 The protocol for the study:

 PROOF OF CONCEPT STUDY: to investigate the effect of Peko-D Forte (100% Hypoestes rosea
 powder) in Parkinson's Disease using mPower2.0 as a quantitative assessment tool.

 Study Protocol

 Serial Number: Hospital Number:

 1. Name:

 2. Address:

 3. Phone number:

 4. Gender: Male Female

 5. Age (in years) Date of Birth (if known):

 CLINICAL DETAILS:

 6. Age at diagnosis of PD:

 7. DURATION OF DISEASE AT DIAGNOSIS

 8. What are the predominant symptoms? (check all that apply) I) Tremor _______ ii)
 Stiffness _______iii) Slowness ______iv) Postural instability_______

 9. Stage of the disease (from Hoehn and Yahr Scale): _______________ I Unilateral disease
 only II Bilateral mild disease III Bilateral disease + early impairment of postural
 stability IV Severe disease requiring considerable assistance V Confinement to
 wheelchair or bed unless aided

 10. Medical co-morbidities i) Hypertension --------- ii) Diabetes Mellitus________ iii)
 Heart failure_______iv) Chronic lung disease_________ v) Osteoarthritis _______vi)
 Glaucoma______ VII) Others_________________________

 11. Current medications and dosages:

 I) L-Dopa + carbidopa ii) Anticholinesterase iii) DOPA-agonists (specify) iv) Others
 (specify)

 12. Medication Side effects (if any)

 13. Any major disability experienced - Yes No IF Yes, check where check whichever is
 applicable: Cognitive ______ On and off phenomenon_____ Neuropathic pain_________
 Dyskinesia____________ others______________

 WILLINGNESS TO PARTICIPATE IN STUDY: Yes No

 PECKO-D Study

 Objective assessment of motor and non-motor- features in PD patients

 The MDS-sponsored Revision of the Unified Parkinson's Disease Rating Scale

 1. Posture: Instructions to examiner: Posture is assessed with the patient standing erect
 after arising from a chair, during walking, and while being tested for postural reflexes. If
 you notice poor posture, tell the patient to stand up straight and see if the posture
 improves (see option 2 below). Rate the worst posture seen in these three observation points.
 Observe for flexion and side-to-side leaning.

 0: Normal: No problems.

 1. Slight: Not quite erect, but posture could be normal for older person.

 2. Mild: Definite flexion, scoliosis or leaning to one side, but patient can correct
 posture to normal posture when asked to do so.

 3. Moderate: Stooped posture, scoliosis or leaning to one side that cannot be corrected
 volitionally to a normal posture by the patient.

 4. Severe: Flexion, scoliosis or leaning with extreme abnormality of posture.

 2. Global spontaneity of movement (body bradykinesia) Instructions to examiner: This global
 rating combines all observations on slowness, hesitancy, and small amplitude and poverty of
 movement in general, including a reduction of gesturing and of crossing the legs. This
 assessment is based on the examiner's global impression after observing for spontaneous
 gestures while sitting, and the nature of arising and walking.

 0: Normal: No problems.

 1: Slight: Slight global slowness and poverty of spontaneous movements. 2: Mild: Mild global
 slowness and poverty of spontaneous movements. 3: Moderate: Moderate global slowness and
 poverty of spontaneous movements. 4: Severe: Severe global slowness and poverty of
 spontaneous movements.

 3. Rigidity: Instructions to examiner: Rigidity is judged on slow passive movement of major
 joints with the patient in a relaxed position and the examiner manipulating the limbs and
 neck. First, test without an activation maneuver. Test and rate neck and each limb
 separately. For arms, test the wrist and elbow joints simultaneously. For legs, test the hip
 and knee joints simultaneously. If no rigidity is detected, use an activation maneuver such
 as tapping fingers, fist opening/closing, or heel tapping in a limb not being tested. Explain
 to the patient to go as limp as possible as you test for rigidity.

 0: Normal: No rigidity.

 1. Slight: Rigidity only detected with activation maneuver.

 2. Mild: Rigidity detected without the activation maneuver, but full range of motion is
 easily achieved.

 3. Moderate: Rigidity detected without the activation maneuver; full range of motion is
 achieved with effort.

 4. Severe: Rigidity detected without the activation maneuver and full range of motion not
 achieved.

 4. Finger tapping: Instructions to examiner: Each hand is tested separately. Demonstrate the
 task, but do not continue to perform the task while the patient is being tested. Instruct the
 patient to tap the index finger on the thumb 10 times as quickly AND as big as possible. Rate
 each side separately, evaluating speed, amplitude, hesitations, halts, and decrementing
 amplitude.

 0: Normal: No problems.

 1. Slight: Any of the following: a) the regular rhythm is broken with one or two
 interruptions or hesitations of the tapping movement; b) slight slowing; c) the
 amplitude decrements near the end of the 10 taps.

 2. Mild: Any of the following: a) 3 to 5 interruptions during tapping; b) mild slowing; c)
 the amplitude decrements midway in the 10-tap sequence.

 3. Moderate: Any of the following: a) more than 5 interruptions during tapping or at least
 one longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the amplitude
 decrements starting after the 1st tap.

 4. Severe: Cannot or can only barely perform the task because of slowing, interruptions, or
 decrements.

 5. Toe tapping Instructions to examiner: Have the patient sit in a straight-backed chair with
 arms, both feet on the floor. Test each foot separately. Demonstrate the task, but do not
 continue to perform the task while the patient is being tested. Instruct the patient to place
 the heel on the ground in a comfortable position and then tap the toes 10 times as big and as
 fast as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts,
 and decrementing amplitude.

 0: Normal: No problems.

 1. Slight: Any of the following: a) the regular rhythm is broken with one or two
 interruptions or hesitations of the tapping movement; b) slight slowing; c) amplitude
 decrements near the end of the ten taps.

 2. Mild: Any of the following: a) 3 to 5 interruptions during the tapping movements; b)
 mild slowing; c) amplitude decrements midway in the task.

 3. Moderate: Any of the following: a) more than 5 interruptions during the tapping
 movements or at least one longer arrest (freeze) in ongoing movement; b) moderate
 slowing; c) amplitude decrements after the 1st tap.

 4. Severe: Cannot or can only barely perform the task because of slowing, interruptions or
 decrements.

 6. Arising from a chair Instructions to examiner: Have the patient sit in a straight-backed
 chair with arms, with both feet on the floor and sitting back in the chair (if the patient is
 not too short). Ask the patient to cross his/her arms across the chest and then to stand up.
 If the patient is not successful, repeat this attempt up to a maximum of two more times. If
 still unsuccessful, allow the patient to move forward in the chair to arise with arms folded
 across the chest. Allow only one attempt in this situation. If unsuccessful, allow the
 patient to push off using his/her hands on the arms of the chair. Allow a maximum of three
 trials of pushing off. If still not successful, assist the patient to arise. After the
 patient stands up, observe the posture.

 0: Normal: No problems. Able to arise quickly without hesitation.

 1. Slight: Arising is slower than normal; or may need more than one attempt; or may need to
 move forward in the chair to arise. No need to use the arms of the chair.

 2. Mild: Pushes self up from the arms of the chair without difficulty.

 3. Moderate: Needs to push off, but tends to fall back; or may have to try more than one
 time using the arms of the chair, but can get up without help.

 4. Severe: Unable to arise without help.

 7. Gait Instructions to examiner: Testing gait is best performed by having the patient
 walking away from and towards the examiner so that both right and left sides of the body can
 be easily observed simultaneously. The patient should walk at least 10 meters (30 feet), then
 turn around and return to the examiner. This item measures multiple behaviors: stride
 amplitude, stride speed, height of foot lift, heel strike during walking, turning, and arm
 swing, but not freezing. Observe posture for item 1

 0: Normal: No problems.

 1. Slight: Independent walking with minor gait impairment.

 2. Mild: Independent walking but with substantial gait impairment.

 3. Moderate: Requires an assistance device for safe walking (walking stick, walker) but not
 a person.

 4. Severe: Cannot walk at all or only with another person's assistance.

 8. Postural Stability Instructions to examiner: The test examines the response to sudden body
 displacement produced by a quick, forceful pull on the shoulders while the patient is
 standing erect with eyes open and feet comfortably apart and parallel to each other. Test
 retropulsion. Stand behind the patient and instruct the patient on what is about to happen.
 Explain that s/he is allowed to take a step backwards to avoid falling. There should be a
 solid wall behind the examiner, at least 1-2 meters away to allow for the observation of the
 number of retropulsive steps. The first pull is an instructional demonstration and is
 purposely milder and not rated. The second time the shoulders are pulled briskly and
 forcefully towards the examiner with enough force to displace the center of gravity so that
 patient MUST take a step backwards. The examiner needs to be ready to catch the patient, but
 must stand sufficiently back so as to allow enough room for the patient to take several steps
 to recover independently. Do not allow the patient to flex the body abnormally forward in
 anticipation of the pull. Observe for the number of steps backwards or falling. Up to and
 including two steps for recovery is considered normal, so abnormal ratings begin with three
 steps. If the patient fails to understand the test, the examiner can repeat the test so that
 the rating is based on an assessment that the examiner feels reflects the patient's
 limitations rather than misunderstanding or lack of preparedness. Observe standing posture.

 0: Normal: No problems. Recovers with one or two steps.

 1. Slight: 3-5 steps, but subject recovers unaided.

 2. Mild: More than 5 steps, but subject recovers unaided.

 3. Moderate: Stands safely, but with absence of postural response; falls if not caught by
 examiner.

 4. Severe: Very unstable, tends to lose balance spontaneously or with just a gentle pull on
 the shoulders.

 9. Rest tremor amplitude Instructions to examiner: This and the next item have been placed
 purposefully at the end of the examination to allow the rater to gather observations on rest
 tremor that may appear at any time during the exam, including when quietly sitting, during
 walking, and during activities when some body parts are moving but others are at rest. Score
 the maximum amplitude that is seen at any time as the final score. Rate only the amplitude
 and not the persistence or the intermittency of the tremor.

 As part of this rating, the patient should sit quietly in a chair with the hands placed on
 the arms of the chair (not in the lap) and the feet comfortably supported on the floor for 10
 seconds with no other directives. Rest tremor is assessed separately for all four limbs and
 also for the lip/jaw. Rate only the maximum amplitude that is seen at any time as the final
 rating. Extremity ratings

 0: Normal: No tremor.

 1. Slight: < 1 cm in maximal amplitude.

 2. Mild: ≥ 1 cm but < 3 cm in maximal amplitude.

 3. Moderate: ≥ 3 cm but < 10 cm in maximal amplitude.

 4. Severe: ≥ 10 cm in maximal amplitude.

 10. Constancy of rest tremor Instructions to examiner: This item receives one rating for all
 rest tremor and focuses on the constancy of rest tremor during the examination period when
 different body parts are variously at rest. It is rated purposefully at the end of the
 examination so that several minutes of information can be coalesced into the rating.

 0: Normal: No tremor.

 1. Slight: Tremor at rest is present ≤ 25% of the entire examination period.

 2. Mild: Tremor at rest is present 26-50% of the entire examination period.

 3. Moderate: Tremor at rest is present 51-75% of the entire examination period.

 4. Severe: Tremor at rest is present > 75% of the entire examination period.

 Total Score: (out of 40)

 Any abnormality on neurological
 examination?:--------------------------------------------------------------------------------
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 Blood Pressure:

 Pulse:

 Weight:

 Randomization:: A. Active medication: B. Placebo

 Mobile Phone serial number: __________________

 Follow up data:

 I) First review at 8 weeks:

 Date scheduled and time:

 Compliance

 Any reported side effects?: ____________________________________________________

 Any benefits noted subjectively?__________________________________________________

 Other comments: ________________________________________________

 Assess motor performance using the MDS Scale- Record the score_______

 II) 4-week washout period: (No study medications to be administered)

 Any comments________________________________________________

 III) Cross-over for 8 weeks with change of study medications (Placebo to active and vice
 versa)

 Date scheduled and time:

 Compliance

 Any side effects? ____________________________________________________

 Any benefits noted? __________________________________________________

 Other comments: ________________________________________________

 Assess motor performance using MDS scale: Record the score_______

 Study completed: Yes No (If No, give reasons) _____________________

 Date completed:

 Any comments__________________________________________________________

 Name and signature of investigator_____________________________________

 Date: ----------------------------
Inclusion Criteria:

 -  Willing and able to give informed consent.

 -  Willingness and ability to comply with study requirements.

 -  PD diagnosis must be confirmed by bradykinesia plus one of the other cardinal
 signs (resting tremor, rigidity, postural instability) being present.

 -  Age >30 years

 -  Men and women with mild to moderate PD: Hoehn and Yahr scale stages 1 - 3.
 Participants may be on current therapeutic agents (including levodopa, dopamine
 agonists, anticholinergics, amantadine or selegiline) to treat PD symptoms at the
 time of enrollment and may remain on these agents throughout the 5-month study
 period.

 -  Women of childbearing potential (i.e., those not postmenopausal or surgically
 sterile) may participate provided that they are using adequate birth control
 methods for the duration of the study. Women of childbearing potential must have
 a negative pregnancy test at baseline and be non-lactating.

 Exclusion Criteria:

 -  • Subjects with advanced, severe disease, including those with dementia, severe
 osteoarthritis, allergies, stroke, and visual impairment.

 -  Presence of atypical PD syndromes due to drugs (e.g., metoclopramide,
 flunarizine), metabolic identified neurogenetic disorders (e.g., Wilson's
 disease), encephalitis, or other degenerative diseases (e.g., progressive
 supranuclear palsy).

 -  Any clinically significant medical condition (e.g., active neoplasm, angina) or
 laboratory abnormality, which would in the judgement of the investigator
 interfere with the subjects' ability to participate in the study or be followed