Single-dose Potassium Supplementation in Patients With ADHD for Whom the Anesthetic Lidocaine is Ineffective

Single-dose Potassium Supplementation in ADHD Patients With Lidocaine Ineffectiveness

Randomized, controlled, double-blind trial of the effect of a single dose of potassium on ADHD symptoms as measured by changes in measures of symptoms of ADHD correlated with the results of their Lidocaine Effectiveness Test.

Study Overview

• Status: Unknown
• Conditions: ADHD
• Intervention / Treatment: Drug: Potassium Gluconate Oral Capsule; Drug: Placebo oral capsule

Detailed Description

Subjects with a confirmed diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), who are either untreated or poorly controlled with existing ADHD therapy, will be recruited for a single, four-hour session.

Each subject will be tested for lidocaine effectiveness using the application of lidocaine gel to the tongue and assessment by taste.

The subjects will then be assigned to two arms, (1) lidocaine sensitive (effective) or (2) lidocaine insensitive (ineffective), and then randomized as to an intervention of potassium supplementation or a placebo.

Each subject will:

• Complete questionnaires about their history of certain symptoms and a food diary.
• Get an ECG to exclude those with arrhythmias.
• Have their baseline serum potassium tested
• Have measures of ADHD symptoms performed.

Then each subject will receive the intervention of a single dose of the potassium or placebo.

After the wait of one hour, a repeat serum potassium and measurement of symptoms will be performed.

Note; The FDA also requires a Columbia Suicide Severity Rating Scale (C-SSRS) for all ADHD trials

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Clinical Research Center of New Jersey (CRCNJ)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Previously documented ADHD diagnosis
2. Untreated or taking existing ADHD drugs, but symptoms poorly controlled (e.g., symptoms not well managed by amphetamines, including ongoing inattention and impulsivity)

Exclusion Criteria:

1. Well treated with existing ADHD medication
2. Epilepsy
3. IQ less than 80
4. Severe head trauma that led to loss of consciousness for more than an hour or required surgery
5. Birth weight below 5 pounds or 2270 grams
6. Severe autism (milder conditions described as Asperger syndrome or "high-functioning autism" are not excluded)
7. Comorbid psychiatric disorders, such as generalized anxiety disorder, major depressive disorder, schizophrenia and schizoaffective disorder, bipolar disorder, and any co-morbid condition at the discretion of the PI that would interfere with a patient's ability to participate
8. Mouth lesions, known to temporarily interfere with lidocaine effectiveness
9. Renal disease or abnormal kidney function or receiving dialysis
10. An individual has a factor likely to reduce penetrance, including excessive salt loss, such as caked salt on the body after exercise and Cystic fibrosis in a relative suggestive of the individual being a carrier.
11. Heart arrhythmia, known or evident on ECG
12. Known intolerance or allergy to lidocaine
13. Already taking supplemental potassium or renin angiotensin aldosterone inhibitors or other potassium elevating agents (see list below)

Angiotensin Converting Enzyme Inhibitors

1. Alacepril (not available in US)
2. Benazepril (Lotensin)
3. Captopril (trade name Capoten)
4. Cilazapril (Inhibace)
5. Delapril (not available in US)
6. Enalapril (Vasotec/Renitec)
7. Fosinopril (Fositen/Monopril)
8. Imidapril (Tanatril)
9. Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril)
10. Moexipril (Univasc)
11. Perindopril (Coversyl/Aceon/Perindo)
12. Quinapril (Accupril)
13. Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace)
14. Spirapril (Renormax)
15. Temocapril (not available in US)
16. Teprotide (but not active by oral administration and not used in US)
17. Trandolapril (Mavik/Odrik/Gopten)
18. Zofenopril

Angiotensin receptor blockers

1. Azilsartan (Edarbi)
2. Candesartan (Atacand)
3. Eprosartan (Teveten)
4. Fimasartan (Kanarb)
5. Irbesartan (Avapro)
6. Losartan (Cozaar)
7. Olmesartan (Benicar/Olmetec)
8. Telmisartan (Micardis)
9. Valsartan (Diovan)

Aldosterone antagonists

1. Spironolactone (Aldactone)
2. Eplerenone (Inspra)

Renin inhibitors

a. Aliskiren (Tekturna, Rasilez)

Other potassium elevating agents

1. Antibiotics, including penicillin G and trimethoprim
2. Azole antifungals
3. Beta-blockers
4. Herbal supplements, including milkweed, lily of the valley, Siberian ginseng, Hawthorn berries
5. Heparin
6. Nonsteroidal anti-inflammatory medications (NSAIDs)
7. Oral contraceptives containing drospirenone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lidocaine-effective ADHD: Intervention; Single-dose potassium gluconate oral capsule intervention for ADHD subjects for whom lidocaine is effective	Drug: Potassium Gluconate Oral Capsule; Each subject will receive a dose of ~8 mg/kg of potassium. We will be giving a maximum of 14 mEq in a single dose.
Placebo Comparator: Lidocaine-effective ADHD: Placebo; Single-dose placebo oral capsule intervention for ADHD subjects for whom lidocaine is effective	Drug: Placebo oral capsule; Each subject will receive a dose of ~8 mg/kg of a placebo capsule
Active Comparator: Lidocaine-ineffective ADHD: Intervention; Single-dose potassium gluconate oral capsule intervention for ADHD subjects for whom lidocaine is ineffective	Drug: Potassium Gluconate Oral Capsule; Each subject will receive a dose of ~8 mg/kg of potassium. We will be giving a maximum of 14 mEq in a single dose.
Placebo Comparator: Lidocaine-ineffective ADHD: placebo; Single-dose placebo oral capsule intervention for ADHD subjects for whom lidocaine is ineffective	Drug: Placebo oral capsule; Each subject will receive a dose of ~8 mg/kg of a placebo capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of lidocaine ineffectiveness in those with ADHD	Investigator assesses identification and intensity of tastes (such as sweet) before and after application of oral lidocaine gel to the tongue.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Investigator documentation of adverse reactions to either lidocaine or potassium	1-2 hours after intervention
Other discomforts	Investigator documentation of complaints or minor discomforts	1-2 hours after intervention
Change in ADHD-RS questionnaires	The questionnaire is a standard assessment tool for measuring the level of ADHD symptoms. The ADHD-RS-IV is for adults and the ADHD-RSM-5 is for teenagers. This test has been validated for measuring the impact of drugs in ADHD, typically multi-dose, multi-week changes. Since this study is a single-dose, several-hour study, the Investigators will complete only the portions designed to done with the patient and by the clinician; sections designed to be completed by parents and teachers. The results will establish expectations for future multi-dose studies. All scores on a range of None, Mild, Moderate, Severe.; Carelessness; Difficulty sustaining attention in activities; No follow through; Can't organize; Avoids/dislikes tasks requiring sustained mental effort; Loses Important items; Easily distractible; Forgetful in daily activities	Baseline and ~1-2 hours later, 1 hour after intervention
Change in Clinical Global Impression Physician Completed Questionnaire	Clinician-assessed improvement in overall symptoms, using CGI S (severity) as baseline and CGI I (improvement) to track any change. Investigator assesses "Compared to his or her condition at baseline, how much has he or she changed?" Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse	Baseline and ~1-2 hours later, 1 hour after intervention
Change in scores using Quotient ADHD System	The Quotient device (http://www.quotient-adhd.com) tracks scores on 6 factors of motion analysis; 6 factors of attention response; and 8 factors of attention state. The subject plays a diagnostic "video game" and the machine tracks movement of the head, and speed and accuracy of the mouse clicks. The first assessment will serve as a baseline and the assessment post-intervention will measure any changes. (all scores from 0-100) Motion Analysis (including Immobility Duration, Number of movements, displacement, area, spacial complexity, temporal scaling) Attention Response Analysis (including adjusted Accuracy, Omission Errors, Commission Errors, Latency, Variability, Coefficient of Variation for response latency) Attention State Analysis (including number of shifts, Attentive, Impulsive, Distracted, Disengaged, Random, Minimal, Contrary, Overall Results)	Baseline and ~1 hour after intervention

Collaborators and Investigators

• Sponsor: AlkaliDx, Inc.
• Investigators: Principal Investigator: Michael M Segal, MD PhD, PhenoSolve, LLC; Principal Investigator: Mark Mintz, MD, CNNH & CRCNJ

Publications and helpful links

General Publications

• Infante MA, Moore EM, Nguyen TT, Fourligas N, Mattson SN, Riley EP. Objective assessment of ADHD core symptoms in children with heavy prenatal alcohol exposure. Physiol Behav. 2015 Sep 1;148:45-50. doi: 10.1016/j.physbeh.2014.10.014. Epub 2014 Oct 23.
• Levitt JO. Practical aspects in the management of hypokalemic periodic paralysis. J Transl Med. 2008 Apr 21;6:18. doi: 10.1186/1479-5876-6-18. Erratum In: J Transl Med. 2014;12:198. Dosage error in article text.
• Nakai Y, Milgrom P, Mancl L, Coldwell SE, Domoto PK, Ramsay DS. Effectiveness of local anesthesia in pediatric dental practice. J Am Dent Assoc. 2000 Dec;131(12):1699-705. doi: 10.14219/jada.archive.2000.0115.
• Segal MM. We cannot say whether attention deficit hyperactivity disorder exists, but we can find its molecular mechanisms. Pediatr Neurol. 2014 Jul;51(1):15-6. doi: 10.1016/j.pediatrneurol.2014.04.014. Epub 2014 Apr 18. No abstract available.
• Segal MM, Rogers GF, Needleman HL, Chapman CA. Hypokalemic sensory overstimulation. J Child Neurol. 2007 Dec;22(12):1408-10. doi: 10.1177/0883073807307095.
• Segal MM, Douglas AF. Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. J Neurophysiol. 1997 Jun;77(6):3021-34. doi: 10.1152/jn.1997.77.6.3021.
• Teicher MH, Polcari A, Fourligas N, Vitaliano G, Navalta CP. Hyperactivity persists in male and female adults with ADHD and remains a highly discriminative feature of the disorder: a case-control study. BMC Psychiatry. 2012 Nov 7;12:190. doi: 10.1186/1471-244X-12-190.

Helpful Links

• Rozanski RJ, Primosch RE, Courts FJ (1988). Clinical efficacy of 1 and 2% solutions of lidocaine. Pediatr Dent.10:287-90
• Saul R (2014) "ADHD Does Not Exist". HarperCollins.
• Segal MM, Jurkat-Rott K, Levitt J, Lehmann-Horn F (2014) Hypokalemic periodic paralysis - an owner's manual
• Segal MM (2015) Devices, Kits, and Methods for Determining Sensitivity to Anesthetics. US Patent Filing 62/210,747, Filed 09/14/2015

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2018
• Primary Completion (Anticipated): November 4, 2018
• Study Completion (Anticipated): December 31, 2018

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: June 14, 2018
• First Posted (Actual): June 20, 2018

Study Record Updates

• Last Update Posted (Actual): June 20, 2018
• Last Update Submitted That Met QC Criteria: June 14, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Conditions in which lidocaine is ineffective
• Other Study ID Numbers: 2017-01A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: We plan to submit for publication descriptions of what was accomplished, and the evaluations as described in the study, including the incidence of lidocaine ineffectiveness in those with ADHD.
• IPD Sharing Time Frame: When the study is complete
• IPD Sharing Access Criteria: open
• IPD Sharing Supporting Information Type: Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No