STUDY ON AUTISM IN CHILDREN, USING AN UNANI HERBAL NEURO-RESTORATIVE SUPPLEMENT, DAN PROTOCOL AND NEED-BASED MB12, MERCURY CHELATION AND HYPERBARIC AIR THERAPY

Last updated August 26, 2007

Only data that is open to parental scrutiny is given below. Certain Specifics of the study are copyright material, and is meant only for the Investigators and Drugs controller of INDIA, and hence deleted from the write-up below.

Current Status:

  1. Protocol & Proforma: Ready
  2. Drugs, Equipments, Center, Staff selection: Ready
  3. Ethics Committee Approval: Obtained
  4. Permission of Drugs Controller of India: Applied for, pending as of now (August 25, 2007)
Click here to return to Autism page Click here to return to main Map page

INVESTIGATORS

Responsibility Name Designation
Chief Investigator Dr. Arun Mukherjee, MD Sr. Consultant in Medicine, Majeedia Hospital, Hamdard University, Delhi &
Director, FSMHP-UDAAN Autism Project; D-93 Amar Colony, New Delhi-24
Addl. Chief Investigator Dr. Shakir Jamil, MD Prof. & Head, & Dean of Faculty of Medicine, Hamdard University, New Delhi
Co-Investigators Dr. (Ms.) M S Ray, MD Sr. Consultant in Pediatrics, Majeedia Hospital, Hamdard University, New Delhi
Co-Investigators Dr. I C Verma, FRCP, FAAP, FAMS Sr. Consultant & Chairman, Dept. of Genetic Medicine; Sir Ganga Ram Hospital, New Delhi
Co-Investigators Dr. Rajiv Uttam, MRCP Sr. Consultant In Pediatrics & Intensivist, Apollo Hospital, Sarita Vihar, New Delhi
Co-Investigators Dr. Tarun Sahni, MD Sr. Consultant in Medicine & HOD HBOT; Apollo Hospital, Sarita Vihar, New Delhi

PROTOCOL

INTRODUCTION

Definition:

Pervasive Developmental Disorder or PDD is a behavioral disorder of speech, communication, social interaction, and repetitive type compulsive behavior. Autism is a form of PDD. There are five types of PDD's. The most commonly encountered are PDD NOS (pervasive developmental disorder not otherwise specified), Childhood autism, and Asperger's syndrome. All these "different" conditions have common diagnostic and physiologic features but differ slightly by the specific diagnostic criteria.

According to the Autism Society of America: AUTISM is a severely incapacitating lifelong developmental disability that typically appears during the first three years of life. In USA, it is reported to occur in approximately one out of every 166 births. The cause of Autism is still debated, but the consensus of opinion favors a multi-genetic fault that gets manifested and aggravated by an unknown number of environmental and life-style factors.

In childhood autism, the children born apparently normal, begin to deteriorate by age of 1 to 2 years. It always presents before 36 months of age. These children may have some speech, developmental and social interactive regression, usually around 18 months of age.

The diagnosis of childhood autism must meet the specific DSM IV criteria and will therefore present with poor eye contact, pervasive ignoring, language delay, and other features. Per definition, these children will have a severe impairment in speech, communication, or social interaction. Many of them will be completely non-verbal and "in their own world."

Management:

The established and commonly practiced therapy at all Autism Management centers in India, as of today, comprises Standard Therapy: Special Education, Sensory Integration, Speech Therapy and Occupational Therapy. These are classical management techniques for Autism since ages. Most therapists still believe that since the cause is genetic, hence no medical benefit may accrue from any medical oriented approach.

However, the same can be said of diabetes mellitus too, which also is a genetic disease. In managing diabetes, we do not restrict management to only diet and exercise. We also treat all medical pathologies induced by the genetic fault and their resultant complications. We take necessary steps to pre-empt their occurrence with the help of need based Insulin and/or oral hypoglycemic agents, lipid lowering agents, anti-thrombotics, ACE Inhibitors, and other cardiovascular drugs and micronutrient support. By doing so, we enhance longevity, reduce mortality and morbidity and improve overall quality of life of diabetics.

Medical Science has today progressed to a sufficient degree to allow us to tread a similar path for children affected by Autism. Thus, though we cannot alter the basic genetic fault in Autism, we can reverse many of its pathologies and prevent their re-occurrence by suitable medical means.

This observational study is designed to investigate some of the more established need-based early medical interventions in India.

OBJECTIVES

Phase I

Intervene with health control (based on results of tests conducted, intolerances and deficiencies detected) and additional supplementation of a placebo controlled Unani Neuro-restorative health supplement. (Benefits expected in 50 to 60% children only).

Phase II

Detect MTHFR deficiency and hyper-homocysteinaemia and intervene with Vitamin MB12. Those who show positive effects within 3 months to continue to receive the same for 2 years. (Benefits expected in 50 to 60% children only).

Phase III

Detect heavy metal overload, especially mercury and intervene with Chelation till urine challenge and blood levels reach normal values or two years, whichever is less. (Benefits expected in 50 to 60% children only)

Phase IV

Detect perfusion deficiencies in brain using CT-cum-SPECT Fusion Scan, and intervene where necessary with low pressure Hyperbaric air (not oxygen). (Benefits expected in 50 to 60% children only)

Medical Interventions proposed

Unani Neuro-restorative Herbal Supplement
Vitamin MB12 Therapy

One of the genetic-induced deficiencies seen in about 2/3rd of Autism cases is deficiency of the key enzyme Methylene Tetra Hydro Folate Reductase (MTHFR).

  1. Deficiency of Vitamin MB12 manufacture leads to defective neural activity as well as Glutathione deficiency. Blood MTHFR levels can be tested at Delhi
  2. Glutathione is responsible for Free Radical Scavenging action at the intracellular level, and for removing heavy metals accumulation from brain cells.
  3. Vitamin MB12 has very negligible storage in the body. It has to be administered such that Any dose given by oral, IM or IV route reaches peak blood levels very fast and is excreted in urine within a few hours only. This is not conducive to it maintains a sustained flat blood level of vitamin MB12 throughout the 24 hours.
Mercury Chelation Therapy

Mercury poisoning resembles Autism in many aspects. Epidemiological studies in US, using the VAERS Database, have shown that there is a distinct possibility that mercury in Thimerosal preservative used in multidose vaccine vials may have neurological adverse effects in some children (1 in 166), due to genetic inability to excrete mercury and other heavy metals efficiently

Low pressure Hyperbaric Therapy

Research at USA based on SPECT and FMRI Scans have proved that there is inflammation and swelling inside the brain of children with Autism. This generic pathology is manageable by low pressure hyperbaric Therapy

MATERIALS AND METHODS

Children with Autism will be selected from those visiting the Outpatient Departments of Majeedia Hospital, Shubham Hospital, and the FSMHP-UDAAN center at D-93 Amar Colony, Lajpatnagar - 24, New Delhi. The latter center is dedicated to help children with autism using Standard Therapy and general health guidelines, including dietary guidance, avoidance of foods that do not suit the child, administration of standard vitamin and mineral supplementations, and isolation and treatment of inter-current infections if any. Hence the main study and follow up will be organized through FSMHP-UDAAN. This study will attempt to see what early medical interventions help an Indian autistic child in the Indian setting.

Phase I: Preliminary Health Improvements phase before starting actual study.

Phase II: After 3 months or more, after Investigators decide health is optimum, MB12 Administration after necessary check-ups

Phase III: After another 3 months or more, after the child stabilizes, Mercury and other heavy metal chelation, with mandatory 3 monthly extensive checkup, for 2 years

Phase IV: After some weeks, after Investigators feel that the child is stable, 5 rounds of 20 sessions of interrupted low pressure Hyperbaric Air Therapy to be started

The study will conclude after the children receive 24 months of vitamin MB12.

Inclusion Criteria:

Exclusion Criteria:

No. of Test Subjects:

At least 40 and not more than 50.

Duration of Treatment:

30 months.

Tolerance:

Both MB12 and DMPS Chelators are some decades old, with extensive world-wide experience. MB12 is already being used all over India freely. Intensive evaluation of tolerance as these drugs will be used in children on a [prolonged basis.

Analysis:

The data will be analyzed using standard statistical methods to assess the benefit to risk ratio.

Schedule of Assessments

Every 3 months, with detailed clinical assessment and biochemical profile as per the phase of the study, plus video recording from the start of Phase II.

CLINICAL FOLLOW UP RECORD

Clinical Assessment:

Necessary check up scales including CARS, etc. to assess degree of ASD trait, Special Education, GMFM, speech, sensory integration, etc.

Laboratory Assessments: Standard, Every 3 months

Laboratory Assessments: Specific for Phase I

Laboratory Assessments: Specific for Phase II

Laboratory Assessments: Specific for Phase III: During Chelation Phase, EVERY 3 MONTHS

PROFILE OF THE INVESTIGATOR

Full name, address and title of the Principal Investigator or Investigator(s) when there is no Principal Investigator:

Name and address of the medical college, hospital or other facility where the clinical trial will be conducted:

Education, Training & Experience that qualify the Investigator for the clinical trial (Attach details including Medical Council registration number, and / or any other statement(s) of qualification(s)):

Name and address of all clinical laboratory facilities to be used in the study.

Name and address of the Ethics Committee that is responsible for approval and continuing review of the study.

Institutional Ethics Committee, Hamdard University, New Delhi (N.B. Approval Obtained on 3rd April 2007)

Names of the other members of the research team (Co- or sub-Investigators) who will be assisting the Investigator in the conduct of the investigation (s).

  1. Addl. Chief Investigator: Prof. Shakir Jamil, Head & Dean of Faculty of Medicine, Hamdard University, Delhi
  2. Dr. Madhusmita Som Ray, Sr. Consultant in Pediatrics, Majeedia Hospital, Hamdard University, New Delhi
  3. Dr. Rajiv Uttam, Sr. Consultant in Pediatrics & Intensivist, Apollo Hospital, New Delhi
  4. Dr. I C Verma, HOD Genetics, Sir Ganga Ram Hospital, Delhi
  5. Dr. Tarun Sahni, Sr. Consultant in Medicine & HOD of Hyperbaric Medicine, Apollo Hospital, New Delhi

Protocol Title and Study number (if any) of the clinical trial to be conducted by the Investigator.

Commitments:

  1. I have reviewed the clinical protocol and agree that it contains all the necessary information to conduct the study. I will not begin the study until all necessary Ethics Committee and regulatory approvals have been obtained.
  2. I agree to conduct the study in accordance with the current protocol. I will not implement any deviation from or changes of the protocol without agreement by the Sponsor and prior review and documented approval / favorable opinion from the Ethics Committee of the amendment, except where necessary to eliminate an immediate hazard(s) to the trial Subjects or when the change(s) involved are only logistical or administrative in nature.
  3. I agree to personally conduct and/or supervise the clinical trial at my site.
  4. I agree to inform all Subjects, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent and Ethics Committee review and approval specified in the GCP guidelines are met.
  5. I agree to report to the Sponsor all adverse experiences that occur in the course of the investigation(s) in accordance with the regulatory and GCP guidelines.
  6. I have read and understood the information in the Investigator's brochure, including the potential risks and side effects of the drug.
  7. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are suitably qualified and experienced and they have been informed about their obligations in meeting their commitments in the trial.
  8. I agree to maintain adequate and accurate records and to make those records available for audit / inspection by the Sponsor, Ethics Committee, Licensing Authority or their authorized representatives, in accordance with regulatory and GCP provisions. I will fully cooperate with any study related audit conducted by regulatory officials or authorized representatives of the Sponsor.
  9. I agree to promptly report to the Ethics Committee all changes in the clinical trial activities and all unanticipated problems involving risks to human Subjects or others.
  10. I agree to inform all unexpected serious adverse events to the Sponsor as well as the Ethics Committee within seven days of their occurrence.
  11. I will maintain confidentiality of the identification of all participating study patients and assure security and confidentiality of study data.
  12. I agree to comply with all other requirements, guidelines and statutory obligations as applicable to clinical Investigators participating in clinical trials

WRITE-UP FOR INFORMED CONSENT TO BE GIVEN TO ALL PARENTS PRIOR TO START OF PHASE II STUDIES

(Phase I studies are a routine protocol advisable for all children with autism visiting our center, whether or not a part of the reseach project)

1.1

Essential Elements:

  1. Statement that the study involves research and explanation of the purpose of the research
    Children with Autism develop mental impairment as a symptom of their brain lesions. Bramhi, supported by certain herbal adjuvants has been used in India for thousands of years as a Neuro-restorative herbal supplement. This will be given to all children and their Cognitive benefits assessed at periodic intervals.
    Majority of autistic children have deficiency of Vitamin Methyl B12 (MB12) activity due to genetic deficiency of the enzymes to deal with Methylation processes (attaching a methyl fraction to Vitamin B12 molecule) and Homocysteine metabolism, which can be assessed to a degree by estimation of Methylene Tetra Hydro Folate Reductase (MTHFR) Enzyme and Homocysteine levels. Deficient MB12 activity is associated with reduced formation of Methionine, reduced methyl radical donation to the RNA / DNA signaling mechanisms and reduced Glutathione production. Both the latter mechanisms are closely linked to the abnormal brain functions seen in Autism, as well as reduced Free radical scavenging action and reduced removal processes for bringing out mercury from inside brain cells so that they may get excreted in urine, especially if a metal chelating agent is also used.
    Your child will be tested for MTHFR activity and Homocysteine levels, and based on results received, we may feel that the child may benefit from Vitamin MB12 supplementation. This is a research study and no positive results are assured, even though we feel, that if confirmed by test results, your child will show a good degree of attenuation of his abnormal behavior after 12 weeks.
    Your child will also be later on tested for heavy metal overload in his body. If these tests prove positive, we would like to give him oral DMPS capsules, a standard heavy metal removing agent, licensed all over Europe and UK for the same.
    Your child will also receive a SPECT Scan of brain, and if our panel of experts feel that Hyperbaric Therapy may benefit the child in repairing his/her inflamed and edematous brain with its defective perfusion, then the child may receive Hyperbaric Therapy, if duly declared medically fit for the same by our pediatrician and ENT Specialist on UDAAN's medical panel.
  2. Expected duration of the Subject's participation
    The expected duration of the Observational Study is 2 to 3 years, starting with Phase I, and progressing on a need based manner right up to Phase IV. Those children who need a particular therapy, will be given the same at a highly subsidized cost (for drug as supplied by the manufacturer, tests at concession available to UDAAN by various laboratories, Hyperbaric Therapy at concession either at UDAAN or Apollo Hospital as per need, and Standard Therapy if the parent wants, at UDAAN at our usual concession for such children.
  3. Description of the procedures to be followed, including all invasive procedures: Each child will be tested for standard biochemical tests for health management, liver function, Kidney function, Hemogram, stool tests for infections, inborn errors of metabolism, some tests for genetic defects as prevalent in our country, Allergy panel, MTHFR and Homocysteine levels in blood, and tests in blood and urine for evidence of heavy metal overload.
    In children who show low MTHFR levels, Vitamin MB12 will be administered at a dose of 64.5 mg/kg subcutaneously every third day. We expect the average dose to be 1.5 to 2 mg each. To facilitate injection, the vitamin is being especially formulated for this study as a 10 mg/ml (= 0.15 to 0.2 ml by volume only), as available in USA for such purposes. The drug will be a Thimerosal free injection, to be administered using an Insulin syringe (6 to 8 markers on the 40 Units/ml syringe), into the subcutaneous fat in the low vascular low sensitive buttocks area. If the child improves within the expected 12 weeks, then in future we will try to enhance facilitation of the injection with a 25 mg/ml solution, so that the injection volume can be further reduced, giving better tolerance as well as improved sustained blood levels over 3 days per shot. This newer formulation will be made available when the manufacturer can deliver it to us.
    Children who show evidence of mercury or other heavy metal overload will be treated with oral DMPS capsules at a dose of 5 to 10 mg/kg/day, for 3 days, followed by a gap of 11 days, for 24 such cycles.
    Children who show abnormal SPECT Scan, will receive low pressure Hyperbaric normal air for 90 minutes per day, at a pressure equal to that felt at a depth of 11 feet of water (deep end of a swimming pool) once a day, for 20 days, followed by a gap of 2 months, for 5 such cycles.
  4. Description of any reasonably foreseeable risks or discomforts to the Subject
    The use of MB12 in children who need it, is associated with revival of the sensory inputs from periphery to brain. Initially, we expect the child to be overwhelmed by the high flow of sensory inputs, much like a partially deaf person using a Hearing Aid for the first time. He hears only extraneous noise. It takes that person 4 to 6 weeks to learn to handle the sensory enhancement. Filter out "noise" and start hearing conversation.
    International experience suggests that sensory arousal takes place as per length of nerve, i.e. face first, then arms and then legs. Hence, initially there would be high irritability in face and tongue, making the child hyperactive and feel like biting and chewing everything. Similar exaggerated activity and irritability would follow in limbs. The child will learn to control the sensory overload within 6 weeks and then start improving.
    The use of DMPS is usually well tolerated. A few children may occasionally witness adverse effects like chills, fever, or cutaneous reactions, presumably of an allergic nature, like itching or rashes (erythema), which usually are reversible once the treatment is stopped. Severe allergic dermatological reactions (e.g erythema exudativum multiforme, Stevens-Johnson syndrome) have been described in a few isolated cases. Particularly when used over a long period of time, DMPS may influence the body's mineral balance especially that of the elements zinc and copper. That is why your child will be re-assessed and tested for his standard biochemical parameters, and levels of normal metals, every 3 months for the duration of oral DMPS therapy. The administration of DMPS mobilizes the ingested mercury in the body. In a few cases this may trigger the clinical symptoms of mercury poisoning. Sickness or vomiting rarefy appear after ingestion of DMPS.
    Low Hyperbaric Therapy is rarely associated with pain or discomfort to ear. It can be avoided if such therapy is avoided during periods of respiratory or other illnesses. A few children or their accompanying adult attendant may feel claustrophobic inside the chamber. In such cases, Hyperbaric therapy may be withdrawn for that person.
  5. Description of any benefits to the Subject or others reasonably expected from research. If no benefit is expected Subject should be made aware of this.
    Studies in US have shown that with carefully selected cases of autism, about 60% of children may show good benefit in reducing their CARS Score, become more sociable, communicative, better at cognitive and Psycho-social skills, and return to society as near normal individuals. Many would become more manageable, with less tantrums, unsocial behavior and improved ADL skills. All children will not respond, and their percentage may be 25 to 40 % as per US reports. These children may be identifiable within the first 6 to 8 months of therapy, in which they may be withdrawn from the study in consultation with the medical panel and the parents concerned./LI>
  6. Disclosure of specific appropriate alternative procedures or therapies available to the Subject.
    Some children who cannot tolerate or respond to Vitamin MB12, may respond to Betaine + Choline supplementation, which is an alternate pathway for Methionine synthesis. Unfortunately, this combination is not easily available in India for long term usage.
    Some children, who do not respond to oral DMPS chelation, may respond to oral DMSA or EDTA chelation. Unfortunately, these drugs are not available in India as of now. Children with severe forms of brain damage as per their SPECT Scan may require Hyperbaric Oxygen Therapy at 1.5 ATA with 100% oxygen for an hour. Such therapy is available at Apollo Hospital at 25% concession to children referred by UDAAN.
  7. Statement describing the extent to which confidentiality of records identifying the Subject will be maintained and who will have access to Subject's medical records.
    The records of the subject will be available to:
  8. Trial treatment schedule(s) and the probability for random assignment to each treatment (for randomized trials)
    Each child will first be assessed at FSMHP UDAAN and his/her general health and infections if any controlled. Routine nutritional supplements will be given along with proper dietary counseling, based on studies of Inborn Errors of Metabolism and history of food intolerance and allergy if any.
    From this pool of healthy infection free children, the children who are found deficient in MTHFR will be initiated into the Phase II Vitamin MB12 study. Those who test positive for heavy metal overload will be initiated into the phase III Heavy metal chelation study. Those children who show evidence of ischemic pathology in SPECT Scan of Brain, will be initiated into the Low Pressure Hyperbaric air therapy.
    Since each phase of therapy is a need based biochemical approach, hence randomization will not be done.
    However, in the Phase IV Hyperbaric Phase, children will be randomly divided into 3 batches, to receive that therapy in sequence, as it is not possible to treat all 40 children simultaneously due to logistic problems
  9. Compensation and/or treatment(s) available to the Subject in the event of a trial-related injury
  10. An explanation about whom to contact for trial related queries, rights of Subjects and in the event of any injury
    Dr. Arun Mukherjee, MD, Sr. Consultant in Medicine, Majeedia Hospital, Hamdard University, and Director: FSMHP-UDAAN and team Leader of the UDAAN Autism Project.
  11. The anticipated prorated payment, if any, to the Subject for participating in the trial.
    No payment is envisaged for participants in the trial.
  12. Subject's responsibilities on participation in the trial
    This study attempts to answer whether properly selected Indian children with autism can benefit from:
    1. Phase I
      • Detailed assessment to discover Inborn Errors of Metabolism and take remedial action / precautions to limit their damage
      • Discover food intolerances and allergies if any and take remedial measures in diet and lifestyle to avoid the same
      • Discover the deficiencies in micronutrients, Hemogram, liver and kidney functions and manage them in classical established methods
      • Discover and treat intercurrent infections, especially of the gut, to improve the prognosis and status of the child
    2. Phase II
      • Discover if the child has deficiency of Methylene Tetra Hydro Folate Reductase (MTHFR) and resultant Hyper-Homocysteinemia, and if found, is there any improvement by giving subcutaneous Vitamin MB12 injections to maintain a flat blood levels of the vitamin to enhance methionine formation and Glutathione regeneration
    3. Phase III
      • Discover if the child is overloaded with mercury using the oral DMPS Challenge Urine mercury excretion testing, and whether the child's autistic symptoms improve with the administration of oral DMPS to chelate mercury and other toxic heavy metals from their body
      • Discover if oral DPMS can cause deficiency of other necessary metals in properly fed diet controlled autistic children; the earlier study by Prof. DN Guha Majumdar in Arsenic Poisoning cases in Bengal had shown that such is not the case, and only those with pre-existing zinc deficiency went into low levels of zinc unless supplemented
    4. Phase IV
      • Discover if SPECT-cum-CT Fusion Scan of Brain of autistic children show ischemic changes, and whether the same improves with low pressure (1.3 ATA) hyperbaric normal air. Those children with more severe forms of ischemic encephalopathy will receive the option of going for regular 1.5 ATA hyperbaric therapy using 100% pure oxygen for 1 hour, once a day.
        The Parent / Guardian of the child with autism will undertake to sincerely try and complete the total envisaged follow up with assurance to continue adequate Standard Therapy at any good center, unless there is a good reason to withdraw from the study. This is in the interests of helping future generations of similarly affected autistic children in India, for whom no guidelines exist as of now on isolating and managing genetic and acquired pathologies, to improve the quality of life of these children as well as of their families.
        The parent will undertake to pay user charges for assessment, cost of drug, and tests at various laboratories of repute, as mentioned earlier.