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Enrolling by Invitation

NCT Number: NCT07640503

Lamivudine as a Novel Clinical Effort for Rett Syndrome

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder caused primarily by mutations in the MECP2 gene, leading to progressive impairments in motor function, communication, and behavior following an initial period of apparently typical development. Currently, there are no treatments that change the course of the disease, and clinical care is largely focused on managing symptoms. Loss of MeCP2 function has been associated with increased activity of the LINE-1 (L1) retroelement, which may contribute to neuroinflammation and cellular stress in the brain. Lamivudine, a nucleoside reverse transcriptase inhibitor widely used in antiviral therapy, can inhibit L1 reverse transcription and has shown beneficial effects in preclinical models of RTT, including reductions in inflammatory and oxidative stress markers and improvements in neurological and behavioral outcomes. This study aims to evaluate the safety and potential clinical and biological effects of lamivudine in individuals with Rett syndrome using a before-and-after treatment design. Participants will receive oral lamivudine and will undergo clinical assessments and laboratory testing before and after the treatment period to evaluate changes in symptom severity, functional status, quality of life, seizure activity, and biomarkers related to inflammation and neurodevelopment. Biological samples will also be collected to support translational laboratory studies aimed at improving understanding of disease mechanisms and treatment response in RTT. Results from this study may help determine whether lamivudine is a safe and promising therapeutic option and may guide future clinical research in this population.

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Key information

Conditions

Rett Syndrome Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Genetic Diseases, X-Linked Heredodegenerative Disorders, Nervous System Intellectual Disability Nervous System Diseases Neurobehavioral Manifestations Neurologic Manifestations X-Linked Intellectual Disability

Age range

2 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 2

Primary location

GenClinics

Fortaleza, Ceará, Brazil

About this study

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder caused primarily by loss-of-function mutations in the MECP2 gene, leading to progressive impairments in motor, cognitive, and communicative function after an initial period of apparently typical development. Currently, there are no medications that change the course of the disease, and treatment is mainly focused on managing symptoms.

Functional MeCP2 represses the activity of the LINE-1 (L1) retroelement, and loss of this repression may result in increased L1 accumulation in glial cells in the brain, promoting genomic instability, oxidative stress, and neuroinflammation associated with RTT pathophysiology.

Lamivudine inhibits L1 reverse transcription and has shown beneficial effects in preclinical neuronal culture and MeCP2-deficient mouse models, including reduced inflammatory and oxidative stress markers, improved neurological and behavioral outcomes, and increased survival. In this study, each participant is evaluated before and after receiving treatment, allowing changes to be assessed within the same individual over time. Following screening and baseline assessments, participants enter a treatment phase during which oral lamivudine is administered for a defined period. Longitudinal clinical, laboratory, and safety evaluations are conducted at scheduled visits, followed by a post-treatment follow-up period to assess the persistence of effects.

A 24-week intervention period was selected as a feasible and acceptable duration for participants and caregivers and as an appropriate timeframe for an initial open-label evaluation of therapeutic potential. This duration is expected to provide sufficient exposure to lamivudine to allow detection of short-term clinical and biological changes suggested by preclinical studies, while also enabling systematic assessment of safety and tolerability in this population.

Participants may continue their usual medical treatments, including medications for seizures and other supportive therapies, as long as these treatments remain stable during the study, unless a change is medically necessary.

Caregivers receive standardized instructions on medication administration, and adherence is monitored throughout the treatment phase through caregiver reporting and visit-based verification to ensure accurate assessment of treatment exposure.

Clinical assessments employ validated clinician and caregiver-reported instruments to evaluate symptom severity, functional status, quality of life, and seizure activity, capturing changes across motor, behavioral, and daily functioning domains relevant to RTT. Safety is monitored continuously through adverse event surveillance, routine clinical evaluations, and laboratory testing, with predefined criteria for treatment interruption if clinically indicated. Venous blood samples are collected at baseline and during treatment to evaluate systemic biomarkers related to oxidative stress, inflammation, and neurodevelopment. These measures complement clinical outcomes and explore potential mechanistic effects of lamivudine treatment.

In addition to the biomarkers reported as outcome measures, a panel of exploratory, hypothesis-generating biomarkers will be analyzed, including markers of oxidative stress, neuroinflammation and neurodevelopment, mitochondrial and energy metabolism, and nutritional and micronutrient status. These analyses are not considered clinical endpoints and are not reported as outcome measures.

As a translational research component, skin punch biopsies from a subset of participants are used to establish a dermal fibroblast biobank, enabling the generation of patient-derived induced pluripotent stem cells and brain organoids. These models will be used in exploratory laboratory studies to investigate cellular and molecular mechanisms in RTT and responses to lamivudine, without being considered clinical endpoints. Based on preclinical evidence and the proposed mechanism of action, lamivudine treatment is expected to be safe and well-tolerated in individuals with Rett syndrome. Clinically, it may lead to improvements in motor function, social engagement, and overall symptom severity, while reducing seizure frequency and enhancing quality of life. Biologically, lamivudine is anticipated to modulate oxidative stress and inflammatory pathways, potentially restoring a more balanced neurodevelopmental environment. The combined clinical and laboratory observations from this study will provide critical insights into the therapeutic potential of lamivudine and inform future research directions in RTT.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Clinical and molecular diagnosis of Rett syndrome;
  • Age 2 years or older at the time of enrollment;
  • Ability to swallow liquid medication;
  • Stable clinical condition, as determined by the study investigator;
  • Availability of a parent or legal guardian able to provide informed consent and comply with study procedures;
  • Willingness of the participant and/or legal guardian to comply with study visits and assessments.

Exclusion criteria

  • Known hypersensitivity or contraindication to lamivudine;
  • Severe hepatic or renal impairment that, in the investigator's judgment, would preclude safe participation;
  • Use of investigational drugs or participation in another clinical trial within a defined washout period before enrollment;
  • Presence of any medical condition or acute illness that could interfere with study participation or outcome assessment, as determined by the investigator;
  • Inability to undergo blood collection or skin biopsy procedures required for the study;
  • Any condition that, in the opinion of the investigator, would place the participant at undue risk or compromise adherence to the study protocol.

Treatment and study plan

Lamivudine

Drug

Lamivudine will be given orally to participants with Rett syndrome using weight-based dosing after baseline clinical and laboratory assessments. Children <14 kg will receive oral solution at 4 mg/kg twice daily (max 300 mg/day). Participants ≥14 kg will receive tablets by weight: 14-20 kg, 150 mg/day; 20-25 kg, 225 mg/day; >25 kg, 300 mg/day. Medication may be taken with or without food. Tablets should not be crushed unless swallowing is difficult. If needed, they may be crushed and mixed with liquid or soft food and taken immediately, or oral solution may be used. Caregivers will be instructed on dosing and concomitant medications. Treatment lasts 24 weeks with weekly safety, tolerability, and efficacy monitoring. Dose adjustment or discontinuation may occur if significant adverse events arise.

Primary outcomes

  1. Change in Rett Syndrome Symptom Severity (RARS)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in Rett syndrome symptom severity assessed using the Rett Assessment Rating Scale (RARS), comparing total scores obtained at baseline with scores obtained after treatment with lamivudine and at post-treatment follow-up. Total scores range from 0 to 128, with higher scores indicating greater symptom severity. A reduction in total score will be interpreted as clinical improvement.

    Unit of Measure: Units on a scale (0-128)

  2. Change in Rett Syndrome Behavioral Symptoms

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in Rett syndrome behavioral symptoms assessed using the Rett Syndrome Behaviour Questionnaire (RSBQ), comparing total scores obtained at baseline with scores obtained at the end of treatment with lamivudine and at post-treatment follow-up. The RSBQ is a Rett syndrome-specific instrument used to assess behavioral, autonomic, and functional manifestations associated with Rett syndrome, including breathing abnormalities, irritability, anxiety, mood, repetitive hand movements, communication, and social interaction.

    The RSBQ consists of 45 items scored from 0 to 2, where 0 indicates "not true," 1 indicates "somewhat or sometimes true," and 2 indicates "often true" or "very true." Total scores range from 0 to 90, with higher scores indicating greater frequency or severity of behavioral symptoms and worse clinical status. A reduction in total score after treatment will be interpreted as improvement in Rett syndrome behavioral symptoms.

    Unit of Measure: Units on a scale (0-90)

  3. Safety of Lamivudine: Occurrence of Adverse Events

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Safety assessed by the number and proportion of participants experiencing at least one adverse event (serious or non-serious) during treatment with lamivudine, based on clinical assessment and laboratory monitoring.

    Unit of Measure: Number and proportion of participants with adverse events

Secondary outcomes

  1. Causality of Adverse Events (LCAT)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Causality of adverse events related to lamivudine assessed using the Liverpool Adverse Drug Reaction Causality Assessment Tool (LCAT). The tool classifies the causal relationship between the drug and each adverse event as unlikely, possible, probable, or definite. Higher categories indicate a greater likelihood of a causal relationship between the adverse event and lamivudine.

    Unit of Measure: Number and proportion of adverse events in each causality category

  2. Change in Health-Related Quality of Life: Pediatric Participants (PedsQL Neuromuscular Module)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in health-related quality of life assessed primarily by the PedsQL 3.0 Neuromuscular Module (PedsQL NMM), caregiver-report adapted version, comparing baseline scores with scores at the end of treatment and at follow-up. The PedsQL NMM yields transformed scores from 0 to 100; higher scores indicate better health-related quality of life and lower symptom impact. An increase after treatment is interpreted as improvement.

    Unit of Measure: Units on a scale (0-100)

  3. Change in Health-Related Quality of Life - Adult participants (SF-36)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in health-related quality of life assessed by the Short Form (36) Health Survey (SF-36) in adult participants, comparing baseline scores with scores at the end of treatment and follow-up. SF-36 domain scores range from 0 to 100, with higher scores indicating better quality of life. An increase in score after treatment is interpreted as improvement.

    Unit of Measure: Units on a scale (0-100)

  4. Change in Adaptive Behavior (Vineland Adaptive Behavior Scales - Adaptive Behavior Composite)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in adaptive behavior assessed using the Vineland Adaptive Behavior Scales, reported as the Adaptive Behavior Composite standard score, comparing baseline with end-of-treatment and follow-up values. Standard scores have a mean of 100 and a standard deviation of 15, higher scores indicate better adaptive functioning.

    Unit of Measure: Standard score

  5. Presence of Epileptic Seizures

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Presence of epileptic seizures during treatment with lamivudine, assessed by the number of participants experiencing at least one epileptic seizure after the start of the intervention. Data obtained from caregiver records and clinical assessment by the research team.

    Unit of Measure: Participants

  6. Frequency of Epileptic Seizures

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in the frequency of epileptic seizures, comparing the mean number of seizures per participant at baseline with the mean number recorded during treatment with lamivudine. Information obtained from a caregiver-completed seizure diary, confirmed at follow-up visits.

    Unit of Measure: Number of seizures per month

  7. Need for Medical Intervention Related to Epileptic Seizures

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Need for medical intervention related to epileptic seizures during treatment with lamivudine, assessed by the number of participants requiring emergency care, hospitalization, or rescue medication due to an epileptic seizure.

    Unit of Measure: Participants

  8. Change in Caregiver Burden (Zarit Burden Interview, ZBI-22)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in caregiver burden assessed using the Zarit Burden Interview (ZBI-22), comparing baseline scores with scores at the end of treatment and at follow-up. Total scores range from 0 to 88, with higher scores indicating greater caregiver burden. A reduction in total score after treatment is interpreted as improvement.

    Unit of Measure: Units on a scale (0-88)

  9. Change in Global Clinical Severity (CGI-S)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in global clinical severity assessed by the Clinical Global Impression Severity (CGI-S) scale, comparing the score at baseline with the score at the end of treatment. The CGI-S is a 7-point clinician-rated scale ranging from 1 to 7, where 1 = normal (not at all ill) and 7 = among the most extremely ill patients. Higher scores indicate greater global clinical severity. A reduction after treatment is interpreted as clinical improvement.

    Unit of Measure: Units on a scale (1-7)

  10. Global Clinical Improvement (CGI-I)

    Time frame: Week 24 and Week 52

    Global clinical improvement assessed using the Clinical Global Impression-Improvement scale (CGI-I) at the end of lamivudine treatment and during post-treatment follow-up. Scores range from 1 ("very much improved") to 7 ("very much worse"), with lower scores indicating greater improvement.

    Unit of Measure: Units on a scale (1-7)

  11. Change in serum C-reactive protein (CRP)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum C-reactive protein (CRP) concentrations, comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/L

  12. Change in serum Monocyte chemoattractant protein-1 (MCP-1)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Monocyte chemoattractant protein-1 (MCP-1), comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: pg/mL

  13. Change in serum Ferritin

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Ferritin, comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: ng/mL

  14. Change in serum Interleukin-1 beta (IL-1β)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Interleukin-1 beta (IL-1β), comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: pg/mL

  15. Change in serum Interleukin-6 (IL-6)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Interleukin-6 (IL-6), comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: pg/mL

  16. Change in serum Interleukin-8 (IL-8)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Interleukin-8 (IL-8), comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: pg/mL

  17. Change in serum Interleukin-10 (IL-10)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Interleukin-10 (IL-10), comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: pg/mL

  18. Change in serum Tumor Necrosis Factor alpha (TNF-α)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Tumor Necrosis Factor alpha (TNF-α), comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: pg/mL

  19. Change in serum Aspartate aminotransferase (AST/TGO)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Aspartate aminotransferase (AST/TGO) levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: U/L

  20. Change in serum Alanine aminotransferase (ALT/TGP)

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Alanine aminotransferase (ALT/TGP) levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: U/L

  21. Change in serum Alkaline phosphatase

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Alkaline phosphatase levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: U/L

  22. Change in serum Urea

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Urea levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/dL

  23. Change in serum Creatinine

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Creatinine levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/dL

  24. Change in serum Glucose

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Glucose levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/dL

  25. Change in serum Uric acid

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum Uric acid levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/dL

  26. Change in serum Total bilirubin

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum total bilirubin levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/dL

  27. Change in serum Direct bilirubin

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum direct bilirubin levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: mg/dL

  28. Change in serum Albumin

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in serum albumin levels comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: g/dL

  29. Change in Hemoglobin

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in hemoglobin comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: g/dL

  30. Change in Hematocrit

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in hematocrit comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: %

  31. Change in Leukocyte count

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in leukocyte count comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: cells/µL

  32. Change in Platelet count

    Time frame: Baseline (Week 0), Week 24 (end of treatment), and Week 52 (post-treatment follow-up)

    Change in platelet count comparing values at baseline with values at the end of treatment and at follow-up.

    Unit of Measure: cells/µL

Sponsors and collaborators

Lead sponsor

Maria Denise Fernandes Carvalho de Andrade

Other

Collaborators

  • University of California, San Diego

Registry information

Official study title

Lamivudine in Individuals With Rett Syndrome: Clinical, Biochemical, and Cellular Evaluation

Acronym: LANCE

Important dates

Study start
2025
Primary completion
2027
Study completion
2027
First posted
Jun 10, 2026
Registry last updated
Jun 10, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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