Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer's Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?

BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

Survey of health planning proposals.

It is important that physicians participate in the debate and planning process that will ultimately guide how we reform the way health care is financed and delivered in the United States. Herein is offered a perspective on the problem, one which is not necessarily appreciated by health planners. While we deliver the best quality of care in the world to most of our population, our system has been severely criticized because we fail to provide for access to a substantial minority of our population. Additionally, the cost of the product is considerably greater than that in comparable countries. Attempts to control costs without diminishing quality have introduced expensive complexities into our system without any real success in cutting costs. Several proposals have been advanced to address the issues of cost and access. One of these is a single payer system, common in Europe and Canada, whereby a single agent or group of agents finances all health care through universal rules and means. A system operating in Hawaii is a simple employer mandate to provide health insurance. A uniquely American plan is the Jackson Hole Plan or Managed Competition (now called "Managed Cooperation"). This system is currently popular among national health planners, and involves a defined minimum managed health plan offered by various groups of providers to employees and individuals through health plan purchasing cooperatives. This plan is interesting, but has not been implemented in any jurisdiction, and it is not certain it would accomplish its goals in practice since it is difficult to predict behavior of all parties to such a system.

[Urinary symptoms in elderly women in nursing homes. Frequency and social consequences of urinary incontinence in elderly women living in nursing homes]. / Urinvejsgener hos gamle plejehjemsboende kvinder. Hyppighed og sociale konsekvenser af urin-inkontinens hos gamle plejehjemsboende kvinder.

All 278 female residents of nursing homes in the County of Roskilde were assessed as regards the extent and severity of urinary incontinence and possible urinary infections. A total of 168 (58.5%) were incontinent. Culture of the urine was performed in 210 women and significant bacteriuria was demonstrated in 50%. Thirty-four out of the total of 287 women (12%) had indwelling catheters. In incontinent women without catheters, great quantities of urine were often voided involuntarily. Despite this, only few were subjectively inconvenienced or inhibited in their social activities. The investigation revealed a connection between urinary incontinence and reduced mobility while no connection was observed with current urinary infections, intake of medicaments and parity. It is emphasized that these results are based on findings in very old women living in nursing homes.

The influence of thymic humoral factor on systemic lupus erythematosus lymphocyte function.

The influence of thymic humoral factor, THF, on systemic lupus erythematosus, SLE, lymphocyte function was investigated. Increasing numbers of SLE T-cells, rosetted at 4 degrees C or 37 degrees C, were cultured with allogeneic normal B-cells and the change in IgM synthesis was assessed. Lymphocytes of some SLE patients showed improved suppression with THF when rosetted at 37 degrees C. Normal control lymphocytes did not show a net change in suppression with THF. The subgroup of SLE patients that showed improved suppression with THF in vitro might be a more appropriate group for in vivo therapeutic trials with thymic hormone, TH, than SLE patients in general.

Therapeutic trial of cryofiltration in patients with rheumatoid arthritis.

Cryofiltration, a new technique for on-line plasma separation and its treatment by cold filtration, enables the selective removal of immune complexes and eliminates the need for replacement proteins. Fifteen patients with rheumatoid arthritis were treated for nine to 10 consecutive sessions over a three- to five-week period. Circulating immune complexes decreased by an average of 78 percent and rheumatoid factor by 32 percent. This was accompanied by significant clinical improvement in morning stiffness, articular index, 50-foot walking time, grip strength, and target joint circumference. Cryofiltration might thus be beneficial for a subgroup of rheumatoid arthritis patients in whom conventional therapy has failed.

Hydrocortisone reverses the suppression of immunoglobulin synthesis by concanavalin A-activated spleen cell supernatants.

Supernatants of concanavalin A (Con A)-activated human spleen cells have been previously shown to inhibit polyclonal immunoglobulin (Ig) biosynthesis by pokeweed mitogen (PWM)-stimulated human spleen and peripheral blood mononuclear cells. In the present study, hydrocortisone was added at the beginning of in vitro culture to determine whether it might influence the immunoregulation of polyclonal IgG, IgA and IgM biosynthesis by PWM-stimulated human spleen and peripheral blood mononuclear cells. Hydrocortisone (10(-5) m) mildly increased (15 +/- 9%; mean +/- s.e.m.) polyclonal Ig biosynthesis when added to PWM-stimulated human mononuclear cells. The addition of supernatants from Con A-activated human spleen cells to PWM-stimulated human spleen and peripheral blood mononuclear cells significantly (P less than 0 . 001) suppressed (94 +/- 2%) polyclonal Ig biosynthesis. In contrast, when hydrocortisone (10(-5) m) was added together with Con A supernatants to PWM-stimulated cells, there was no significant suppression (6 +/- 13%) of polyclonal Ig synthesis. Thus, one mechanism by which hydrocortisone can influence Ig biosynthesis is by blocking the suppressive effect of a soluble suppressor factor secreted by Con A-activated human spleen cells.

Circulating immune complexes in rheumatoid arthritis. Selective removal by cryogelation with membrane filtration.

We have developed a system of extracorporeal circulation that removes proteins of the molecular weight of the circulating immune complexes of rheumatoid arthritis by cryogelation with hollow-fiber membrane filtration. A 52-year-old woman with a 36-year history of severe, unremitting, high-titer, seropositive rheumatoid arthritis who had failed to respond to anti-inflammatory, antirheumatic, and cytotoxic drugs was chosen for a trial of this system. A rapid and sustained decrease in circulating immune complexes as measured by C1q binding occurred, accompanied by a much slower improvement in clinical factors of disease activity. Rheumatoid factor changed very little and loss of other serum proteins by the procedure was relatively modest. This new procedure was successful in removing circulating immune complexes in a patient with rheumatoid arthritis, and in inducing a remission in one who has not had such in 36 years, while sparing volume and other plasma proteins.

Lymphocyte kinetics in pustular psoriasis.

Generalized pustular psoriasis is a potentially lethal variant of psoriasis vulgaris characterized by the appearance of sterile pustules on inflamed psoriatic skin. We now report the finding of an absolute lymphopenia at the onset of pustular psoriasis. While the white blood cell count rises to a level of 25,000 to 40,000 in the initial stages of a pustular flare, the lymphocyte count drops from a normal level to an absolute lymphopenia. This "lymphocyte eclipse," as we have called it, appears to be a reliable sign of impending pustular activity and has now been documented in ten patients with pustular psoriasis. Immediate institution of therapy may abort a potentially lethal complication of psoriasis.

Development of systemic lupus erythematosus after thymectomy for myasthenia gravis. Studies of suppressor cell function.

Systemic lupus erythematosus developed in an 18-year-old man three years after thymectomy for myasthenia gravis. The patient had considerable defects in suppressor cell function that seemed to be partially reversed in vitro by the addition of thymic hormone.

Abnormalities of immunoregulation in progressive systemic sclerosis. Evidence for excess helper-cell function and altered B-cell function.

We investigated immunoregulatory function in patients with progressive systemic sclerosis (PSS) in terms of in vitro IgM synthesis. Suppressor-cell function seems normal in regard to the ability of concanavalin A-treated cells to inhibit IgM synthesis by normal cells. At 4 x 10(5) T cells to 3 x 10(5) allogeneic normal B cells per milliliter, T cells from patients with PSS induce significantly more IgM synthesis by normal B cells than do normal T cells. This increased helper T-cell function might be involved in the pathogenesis of the disease.

Relative reference values for clinical chemical and haematological quantities in 'healthy' elderly people.

A search of the literature revealed a paucity of data on reference values for clinical chemical and haematological quantities in reasonably 'healthy' ambulant persons above 65 years of age. On the basis of 90 papers, concerning 37 different types of quantities, the median values for men and for women at 30, 50, 65, and 80 years are calculated relative to the value in men at 30 years. This transformation reduces influences of analytical and demographic factors that have caused considerable systematic differences in the original data. The reference distribution is described as regards symmetry and the change in dispersion with age. The results are given in a table and show four types of changes with age: no significant variation, a fall, an increase or a maximum somewhere between 30 and 80 years; the type of change often depends on sex.